Charged ion channel blockers and methods for use

ABSTRACT

The invention provides compounds of Formula (I), or pharmaceutically acceptable salts thereof: 
     
       
         
         
             
             
         
       
     
      The compounds, compositions, methods and kits of the invention are useful for the treatment of pain, itch, and neurogenic inflammation.

RELATED APPLICATIONS

This application is a continuation of U.S. Application No. 16/816,018,filed Mar. 11, 2020, which claims the benefit of U.S. ProvisionalApplication Serial No. 62/816,434 filed Mar. 11, 2019 and U.S.Provisional Application Serial No. 62/931,590 filed Nov. 6, 2019. Theentire contents of the above applications are incorporated by referenceherein.

TECHNICAL FIELD

The present invention relates generally to quaternary ammoniumcompounds, pharmaceutical compositions, and methods useful as selectiveinhibitors of pain, cough, and itch sensing neurons (nociceptors, coughreceptors and pruriceptors) and in the treatment of neurogenicinflammation.

BACKGROUND OF THE INVENTION

The invention features compounds, compositions and methods for theselective inhibition of sensory neurons (nociceptors, cough receptorsand pruriceptors) and the treatment of neurogenic inflammation bytargeting nociceptors with a small molecule drug, while minimizingeffects on non-nociceptive neurons or other types of cells. According tothe method of the invention, small, cationic drug molecules gain accessto the intracellular compartment of sensory neurons via entry throughlarge pore receptor/ion channels that are present in pain-cough- anditch-sensing neurons but to a lesser extent or not at all in other typesof neurons or in other types of tissue.

Local anesthetics such as lidocaine and articaine act by inhibitingvoltage-dependent sodium channels in neurons. These anesthetics blocksodium channels and thereby the excitability of all neurons, not justpain-sensing neurons (nociceptors). Thus, while the goal of topical orregional anesthesia is to block transmission of signals in nociceptorsto prevent pain, administration of local anesthetics also producesunwanted or deleterious effects such as general numbness from block oflow threshold pressure and touch receptors, motor deficits and/orparalysis from block of motor axons and other complications from blockof autonomic fibers. Local anesthetics are relatively hydrophobicmolecules that gain access to their blocking site on the sodium channelby diffusing through the cell membrane. Charged derivatives of thesecompounds, which are not membrane-permeable, have no effect on neuronalsodium channels when applied to the external surface of the nervemembrane but can block sodium channels if somehow introduced inside thecell, for example by diffusion from a micropipette used for whole-cellelectrophysiological recording from isolated neurons. Pain-, cough-, anditch-sensing neurons differ from other types of neurons in expressing(in most cases) the TRPV1 receptor/channel, which is activated bypainful heat or by capsaicin, the pungent ingredient in chili pepper.Other types of channels selectively expressed in various types ofpain-sensing, cough-sensing and itch-sensing (pruriceptor) neuronsinclude but are not limited to TRPV2-4, TRPA1, TRPM8, ASIC and P2X(⅔)channels. It is well established that some cationic small molecules suchas QX-314 are able to enter a cell via passage through activated largepore channels such as TRPV1.

Neuropathic, inflammatory, and nociceptive pain differ in theiretiology, pathophysiology, diagnosis, and treatment. Nociceptive painoccurs in response to the activation of a specific subset of highthreshold peripheral sensory neurons, the nociceptors, by intense ornoxious stimuli. It is generally acute, self-limiting and serves aprotective biological function by acting as a warning of potential oron-going tissue damage. It is typically well-localized. Examples ofnociceptive pain include, but are not limited to, traumatic or surgicalpain, labor pain, sprains, bone fractures, burns, bumps, bruises,injections, dental procedures, skin biopsies, and obstructions.

Inflammatory pain is pain that occurs in the presence of tissue damageor inflammation including postoperative (i.e. pain associated with acuteperioperative pain resulting from inflammation caused by tissue trauma(e.g., surgical incision, dissection, burns) or direct nerve injury(e.g., nerve transection, stretching, or compression)), post-traumaticpain, arthritic pain (rheumatoid; or osteoarthritis (i.e. joint pain andstiffness due to gradual deterioration of the joint cartilage; riskfactors include aging, injury, and obesity; commonly affected joints arethe hand, wrist, neck, knee, hip, and spine), pain and pain associatedwith damage to joints, muscle, and tendons as in axial low back pain(i.e. a prevalent, painful condition affecting the lower portion of theback; common causes include muscle strain, spine fracture, bulging orruptured disc, and arthritis), severe nociceptive pain may transition toinflammatory pain if there is associated tissue injury.

Neuropathic pain is a common type of chronic, non-malignant pain, whichis the result of an injury or malfunction in the peripheral or centralnervous system and serves no protective biological function. It isestimated to affect more than 1.6 million people in the U.S. population.Neuropathic pain has many different etiologies, and may occur, forexample, due to trauma, surgery, herniation of an intervertebral disk,spinal cord injury, diabetes, infection with herpes zoster (shingles),HIV/AIDS, late-stage cancer, amputation (including mastectomy), carpaltunnel syndrome, chronic alcohol use, exposure to radiation, and as anunintended side-effect of neurotoxic treatment agents, such as certainanti-HIV and chemotherapeutic drugs. Peripheral neuropathy is caused bydamages to the peripheral nerves from injury, trauma, prolongedpressure, or inflammation causing numbness and pain in correspondingareas of the body.

Neuropathic pain is frequently described as “burning,” “electric,”“tingling,” or “shooting” in nature. It is often characterized bychronic dynamic allodynia (defined as pain resulting from a movingstimulus that does not ordinarily elicit a painful response, such aslight touch) and hyperalgesia (defined as an increased sensitivity to anormally painful stimulus) and may persist for months or years beyondthe apparent healing of any damaged tissues.

Pain may occur in patients with cancer, which may be due to multiplecauses; inflammation, compression, invasion, metastatic spread into boneor other tissues.

There are some conditions where pain occurs in the absence of a noxiousstimulus, tissue damage or a lesion to the nervous system, calleddysfunctional pain and these include but are not limited tofibromyalgia, tension type headache, and irritable bowel disorders.

Migraine is a headache associated with the activation of sensory fibersinnervating the meninges of the brain.

Itch (pruritus) is a dermatological condition that may be localized andgeneralized and can be associated with skin lesions (rash, atopiceczema, wheals). Itch accompanies many conditions including but notlimited to stress, anxiety, UV radiation from the sun, metabolic andendocrine disorders (e.g., liver or kidney disease, hyperthyroidism),cancers (e.g., lymphoma), reactions to drugs or food, parasitic andfungal infections, allergic reactions, diseases of the blood (e.g.,polycythemia vera), and dermatological conditions. Itch is mediated by asubset of small diameter primary sensory neurons, the pruriceptor, thatshare many features of nociceptor neurons, including but not limited toexpression of TRPV1 channels, and other large pore channels (e.g.TRPV2-4, TRPA1, TRPM8, ASIC and P2X(⅔). Certain itch mediators—such aseicosanoids, histamine, bradykinin, ATP, and various neurotrophins haveendovanilloid functions. Topical capsaicin suppresses histamine-induceditch. Pruriceptors like nociceptors are therefore a suitable target forthis method of delivering ion channel blockers.

Cough is a defensive reflex designed to protect the airway from foreignbodies and to aid in the clearance of luminal debris. This reflex,however, can became aberrant in a number of diseases leading to anon-productive dry cough where hyper- or allo-tussive states exist.Hyper- and allo-tussive states are often chronic in nature lastinggreater than three months and can be manifested in many airway diseasesstates including asthma, COPD, asthma-COPD overlap syndrome (ACOS),interstitial pulmonary fibrosis (IPF) and lung cancer. In addition,inappropriate cough reflexes can be manifested acutely and chronicallyfollowing viral infection. Furthermore, chronic cough can be idiopathicin nature with unknown etiology.

Neurogenic inflammation is a mode of inflammation mediated by theefferent (motor) functions of sensory neurons, in which pro-inflammatorymediator molecules released in the periphery by pain-sensing neurons(nociceptors) both activate a variety of inflammatory pathways in immunecells, and also act on the vascular system to alter blood flow andcapillary permeability.

Neurogenic inflammation contributes to the peripheral inflammationelicited by tissue injury, autoimmune disease, infection, allergy,exposure to irritants in a variety of tissues, and is thought to play animportant role in the pathogenesis of numerous disorders (e.g.,migraine, arthritis, rhinitis, gastritis, colitis, cystitis, andsunburn). One way to reduce neurogenic inflammation is to blockexcitability in nociceptors, thereby preventing the activation ofnociceptor peripheral terminals and the release of pro-inflammatorychemicals.

Despite the development of a variety of therapies for pain, itch, andneurogenic inflammation, there is a need for additional agents.

SUMMARY OF THE INVENTION

The present invention provides compounds represented by Formula (I) thatcan be used to treat or prevent pain, itch, and neurogenic inflammation:

wherein:

-   Y⁻ is a pharmaceutically acceptable anion;-   n is 1, 2, 3, or 4;-   R^(A), R^(B), and R^(C) are each independently selected from H, D,    halogen, substituted or unsubstituted alkyl, substituted or    unsubstituted alkenyl, substituted or unsubstituted alkynyl,    substituted or unsubstituted aryl, substituted or unsubstituted    heteroaryl, substituted or unsubstituted cycloalkyl, substituted or    unsubstituted heterocycloalkyl, OR^(I), CN, NR^(J)R^(K),    NR^(L)C(O)R^(M), S(O)R^(N), S(O)₂R^(N), SO₂R^(O)R^(P),    SO₂NR^(Q)R^(R), SO₃R^(S), CO₂R^(T); C(O)R^(U), and C(O)NR^(V)R^(W),    (preferably R^(A) and R^(B) are methyl and R^(C) is H, F, Cl, or CN    and more preferably H);-   each of R^(I), R^(J), R^(K), R^(L), R^(M), R^(N), R^(O), R^(P),    R^(Q), R^(R), R^(S), R^(U), R^(V), and R^(W) is independently    selected from H, D, substituted or unsubstituted alkyl, substituted    or unsubstituted alkenyl, substituted or unsubstituted alkynyl,    substituted or unsubstituted aryl, substituted or unsubstituted    heteroaryl, substituted or unsubstituted cycloalkyl, substituted or    unsubstituted heterocycloalkyl; R^(J) and R^(K) or R^(V) and R^(W)    or R^(Q) and R^(R) can also be taken together with the nitrogen to    which they are attached to form a substituted or unsubstituted 5, 6,    7, or 8 membered ring;-   R^(A), R^(B), and/or R^(C) taken together with the phenyl ring to    which they are attached can form a fused bicyclic or tricyclic ring    system, such as naphthyl, dihydroindenyl, tetrahydronaphthyl,    quinolinyl, indolyl, and the like;-   X¹ is selected from -CR^(X)R^(Y)-, —NR^(Z)C(O)—, —OC(O)—, —SC(O)—,    —C(O)NR^(1A)—, —C(O)O—, —C(O)—, —(O)CS—, —NR^(1A)S(O)—,    —S(O)NR^(1A)—, —NR^(1A)C(O)NR^(1A)—, —S(O)— and —S(O)₂— ; X¹ can    also be —NR^(Z)C(O)CR^(X)R^(Y)—;-   each of R^(X), R^(Y), R^(Z), and R^(1A) is independently selected    from H, D, substituted or unsubstituted alkyl, substituted or    unsubstituted alkenyl, substituted or unsubstituted alkynyl, and    substituted or unsubstituted heteroalkyl;-   each of R^(D) and R^(E) is independently selected from H, D,    substituted or unsubstituted alkyl, substituted or unsubstituted    alkenyl, substituted or unsubstituted alkynyl, substituted or    unsubstituted heteroalkyl, and substituted or unsubstituted    cycloalkyl; or R^(D) and R^(E) together with the carbon to which    they are attached form a substituted or unsubstituted 3-6-membered    cycloalkyl (a C₃-C₆ cycloalkyl), substituted or unsubstituted    heterocyclic, or substituted or unsubstituted heteroalkyl ring;-   or R^(D) and R^(Z) together with the carbon and the —N—C(O)— to    which they are attached form an optionally substituted 5-8-membered    lactam;-   R^(H) is a substituted or unsubstituted alkyl, substituted or    unsubstituted alkenyl, substituted or unsubstituted alkynyl,    substituted or unsubstituted aryl, substituted or unsubstituted    heteroaryl, substituted or unsubstituted cycloalkyl, substituted or    unsubstituted heterocycloalkyl; in certain aspects, R^(H) can be a    substituted or unsubstituted aralkyl or heteroarylalkyl; in    additional aspects, R^(H) can be substituted or unsubstituted    alkylcarboxylate, substituted or unsubstituted alkylcarboxamide; and-   R^(1B) is a substituted or unsubstituted aryl or substituted or    unsubstituted heteroaryl, preferably substituted or unsubstituted    phenyl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds represented by Formula (I) asdescribed above, or pharmaceutically acceptable salts, stereoisomers,solvates, hydrates or combinations thereof. The invention also providescompositions comprising compounds having Formula (I) or apharmaceutically acceptable salts thereof, for example, a compositioncomprising an effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. The compositions of the invention may furthercomprise compounds of the invention and a biologically active agent. Thecompositions can be formulated for oral, intravenous, intramuscular,rectal, cutaneous, subcutaneous, topical, transdermal, sublingual,nasal, inhalation, vaginal, intrathecal, epidural, or ocularadministration.

The invention further provides methods for treating pain, cough, itch,or a neurogenic inflammatory disorder in a patient, includingadministering to the patient a composition comprising a compound havingFormula (I), wherein the compound inhibits one or more voltage-gated ionchannels present in nociceptors and/or cough receptors and/orpruriceptors when exposed or applied to the internal face of thechannels but does not substantially inhibit the channels when applied tothe external face of the channels, and wherein the compound is capableof entering nociceptors, cough receptors or pruriceptors through a largepore channel when the channel is activated and inhibiting one or morevoltage-gated ion channels present in the nociceptors cough receptors orpruriceptors.

In certain embodiments, the large pore channel is a transient receptorpotential ion channel (TRP channel). In other embodiments, the TRPchannel is activated by an exogenous or endogenous agonist. In yet otherembodiments, the large pore channel is TRPA1, TRPV1-4, TRPM8, ASIC orP2X. In particular embodiments, the compound is capable of enteringnociceptors, cough receptors or pruriceptors through the TRPA1 TRPV1-4,TRPM8, ASIC or P2X receptor/channel when the receptor/channel isactivated. In yet other embodiments, the compound inhibits voltage-gatedsodium channels. In yet another embodiment, the type of pain treated bythe methods, compositions, and kits of the invention is selected fromthe group consisting of neuropathic pain, inflammatory pain, nociceptivepain, pain due to infections, and procedural pain, or wherein theneurogenic inflammatory disorder is selected from the group consistingof allergic inflammation, asthma, chronic cough, conjunctivitis,rhinitis, psoriasis, inflammatory bowel disease, interstitial cystitis,and atopic dermatitis.

We have identified compounds having Formula (I)

that are capable of passing through open large pore channels that areexpressed on nociceptors and/or cough receptors and/or pruriceptors butnot on motor neurons. Because the ion channel blocking compounds of thepresent invention are positively charged, they are notmembrane-permeable and thus cannot enter cells that do not express largepore channels. Since large pore channels are often more active in tissueconditions associated with pain (such as inflammation) due to release ofendogenous ligands or activation by thermal stimuli, the ion channelblocker of the invention can be used alone to selectively targetactivated nociceptors in order to effectively treat (e.g., eliminate oralleviate) pain, cough, itch, or neurogenic inflammation. The ionchannel blockers of the invention can also be used in combination withone or more exogenous large pore channel agonists to selectively targetnociceptors in order to effectively treat (e.g., eliminate or alleviate)pain, itch, or neurogenic inflammation.

Voltage-dependent ion channels in pain-sensing neurons are currently ofgreat interest in developing drugs to treat pain. Blockingvoltage-dependent sodium channels in pain-sensing neurons can block painsignals by interrupting initiation and transmission of the actionpotential. Moreover, blocking voltage-dependent sodium channels innociceptors can reduce or eliminate neurogenic inflammation bypreventing activation of nociceptor peripheral terminals and the releasethereof pro-inflammatory chemicals.

Heretofore, a limitation in treating with molecules that block sodiumchannels or calcium channels is that the vast majority of suchexternally-applied molecules are hydrophobic and can pass throughmembranes. Because of this, they will enter all cells and thus have noselectivity for affecting only nociceptors.

The inhibitors of the present invention are membrane-impermeable and areonly effective when present inside the nociceptor cell, and thus mustpass through the cell membrane via a channel or receptor, such as largepore channels (e.g., TRPAV1-4, TRPA1, TRPM8, ASIC and P2X(⅔)), in orderto produce an effect. Under normal circumstances, most large porechannels in nociceptors are not active but require a noxious thermal,mechanical, or chemical stimulus to activate them. For example, TRPchannels in nociceptors can be activated by an exogenous TRP ligand(i.e. TRP agonist) such as capsaicin, which opens the TRPV1 channel.Thus, one approach to selectively targeting nociceptors is toco-administer the membrane-impermeable ion channel inhibitor with anexogenous TRP ligand that permits passage of the inhibitor through theTRP channel into the cell. In addition to capsaicin, the exogenous TRPligand can also be another capsaicinoid, mustard oil, or lidocaine. Inanother example, TRP channels may be active in response to exogenousirritant activators such as inhaled acrolein from smoke or chemicalwarfare agents such as tear gas.

Under certain circumstances, large pore channels can be activated in theabsence of exogenous large pore channel agonists/ligands by endogenousinflammatory activators that are generated by tissue damage, infection,autoimmunity, atopy, ischemia, hypoxia, cellular stress, immune cellactivation, immune mediator production, and oxidative stress. Under suchconditions, endogenous molecules (e.g., protons, lipids, and reactiveoxygen species) can activate large pore channels expressed onnociceptors, allowing membrane-impermeable, voltage-gated ion channelblockers to gain access to the inside of the nociceptor through theendogenously-activated large pore channels. Endogenous inflammatoryactivators of large pore channels include, for example, prostaglandins,nitric oxide (NO), peroxide (H₂O₂), cysteine-reactive inflammatorymediators like 4-hydroxynonenal, endogenous alkenyl aldehydes,endocannabinoids, and immune mediators (e.g., interleukin 1 (IL-1),nerve growth factor (NGF), and bradykinin, whose receptors are coupledto large pore channels).

Definitions

As used herein, the words “a” and “an” are meant to include one or moreunless otherwise specified.

By “biologically active” is meant that a molecule, including biologicalmolecules, such as nucleic acids, peptides, polypeptides, and proteins,exerts a biological, physical or chemical effect activity on a protein,enzyme, receptor, ligand, antigen, itself or other molecule. Forexample, a “biologically active” molecule may possess, e.g., enzymaticactivity, protein binding activity, or pharmacological activities.

Biologically active agents that can be used in the methods and kitsdescribed herein include, without limitation, TRP1A receptor agonists,TRPV1-4 receptor agonists, ASIC agonists, TRPM8 agonists, P2X receptoragonists, NSAIDs, glucocorticoids, narcotics, antiproliferative andimmune modulatory agents, an antibody or antibody fragment, anantibiotic, a polynucleotide, a polypeptide, a protein, an anti-canceragent, a growth factor, and a vaccine.

By “inflammation” is meant any types of inflammation, such those causedby the immune system (immune-mediated inflammation) and by the nervoussystem (neurogenic inflammation), and any symptom of inflammation,including redness, heat, swelling, pain, and/or loss of function.

By “neurogenic inflammation” is meant any type of inflammation mediatedor contributed to by neurons (e.g. nociceptors) or any other componentof the central or peripheral nervous system.

The term “pain” is used herein in the broadest sense and refers to alltypes of pain, including acute and chronic pain, such as nociceptivepain, e.g. somatic pain and visceral pain; inflammatory pain,dysfunctional pain, idiopathic pain, neuropathic pain, e.g., centrallygenerated pain and peripherally generated pain, migraine, and cancerpain.

The term “nociceptive pain” is used to include all pain caused bynoxious stimuli that threaten to or actually injure body tissues,including, without limitation, by a cut, bruise, bone fracture, crushinjury, burn, and the like. Pain receptors for tissue injury(nociceptors) are located mostly in the skin, musculoskeletal system, orinternal organs.

The term “somatic pain” is used to refer to pain arising from bone,joint, muscle, skin, or connective tissue. This type of pain istypically well localized.

The term “visceral pain” is used herein to refer to pain arising fromvisceral organs, such as the respiratory, gastrointestinal tract andpancreas, the urinary tract and reproductive organs. Visceral painincludes pain caused by tumor involvement of the organ capsule. Anothertype of visceral pain, which is typically caused by obstruction ofhollow viscus, is characterized by intermittent cramping and poorlylocalized pain. Visceral pain may be associated with inflammation as incystitis or reflux esophagitis.

The term “inflammatory pain” includes pain associated with activeinflammation that may be caused by trauma, surgery, infection andautoimmune diseases.

The term “neuropathic pain” is used herein to refer to pain originatingfrom abnormal processing of sensory input by the peripheral or centralnervous system consequent on a lesion to these systems.

The term “procedural pain” refers to pain arising from a medical, dentalor surgical procedure wherein the procedure is usually planned orassociated with acute trauma.

The term “itch” is used herein in the broadest sense and refers to alltypes of itching and stinging sensations localized and generalized,acute intermittent and persistent. The itch may be idiopathic, allergic,metabolic, infectious, drug-induced, due to liver, kidney disease, orcancer. “Pruritus” is severe itching.

By “patient” is meant any animal. In one embodiment, the patient is ahuman. Other animals that can be treated using the methods,compositions, and kits of the invention include but are not limited tonon-human primates (e.g., monkeys, gorillas, chimpanzees), domesticatedanimals (e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas), andcompanion animals (e.g., guinea pigs, rats, mice, lizards, snakes, dogs,cats, fish, hamsters, and birds).

Compounds useful in the invention include, but are not limited to, thosedescribed herein in any of their pharmaceutically acceptable forms,including isomers such as diastereomers and enantiomers, salts, esters,amides, thioesters, solvates, and polymorphs thereof, as well as racemicmixtures and pure isomers of the compounds described herein. The term“pharmaceutically acceptable anion” as used herein, refers to theconjugate base of a pharmaceutically acceptable acid. Such acids aredescribed in Stahl, P.H. and Wermuth, C.G. (eds.), Handbook ofPharmaceutical Salts: Properties, Selection and Use, Wiley VCH (2008).Pharmaceutically acceptable acids include, but are not limited to,acetic acid, dichloroacetic acid, adipic acid, alginic acid, L-ascorbicacid, L-aspartic acid, benzenesulfonic acid, 4-acetamidobenzoic acid,benzoic acid, p-bromophenylsulfonic acid, (+)-camphoric acid,(+)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid,carbonic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonicacid, sulfuric acid, boric acid, citric acid, formic acid, fumaric acid,galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid,D-glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrochloric acid,hydrobromic acid, hydroiodic acid, isobutyric acid, DL-lactic acid,lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonicacid, DL-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonicacid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, phosphoric acid, propionic acid, (-)-L-pyroglutamic acid,salicyclic acid, 4-aminosalicyclic acid, sebacic acid, stearic acid,succinic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonicacid, and undecylenic acid. Pharmaceutically acceptable anions includethe conjugate base of any the acids set forth above.

The term “pharmaceutically acceptable salt” represents those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. The salts can beprepared in situ during the final isolation and purification of thecompounds of the invention, or separately by reacting the free basefunction with a suitable organic acid. Representative acid additionsalts include, but are not limited to acetate, adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, isethionate,lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,toluenesulfonate, undecanoate, valerate salts, and the like.

In the generic descriptions of compounds of this invention, the numberof atoms of a particular type in a substituent group is generally givenas a range, e.g., an alkyl group containing from 1 to 4 carbon atoms orC₁₋₄ alkyl of C₁-C₄ alkyl. Reference to such a range is intended toinclude specific references to groups having each of the integer numberof atoms within the specified range. For example, an alkyl group from 1to 4 carbon atoms includes each of C₁, C₂, C₃, and C₄ alkyls. Othernumbers of atoms and other types of atoms may be indicated in a similarmanner.

“D” is Deuterium

As used herein, the terms “alkyl” and the prefix “alk-” are inclusive ofboth straight chain and branched chain groups and of cyclic groups,i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic andpreferably have from 3 to 6 ring carbon atoms or 3 to 7 carbon atoms,inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl groups.

By “C₁₋₄ alkyl” or “C₁-C₄ alkyl” is meant a branched or unbranchedhydrocarbon group having from 1 to 4 carbon atoms. Similarly, a “C₁₋₆alkyl” or “C₁-C₆” is a branched or unbranched hydrocarbon group havingfrom 1 to 6 carbon atoms. An alkyl, including, for example, a C₁₋₄ alkylor C₁₋₆ alkyl group may be substituted or unsubstituted. Exemplarysubstituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio,halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, alkylamino,disubstituted amino, quaternary amino, alkylcarboxy, alkylcarboxylate,alkylcarboxamide, and carboxyl groups. Exemplary substituents alsoinclude alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl,Br or I), hydroxyl, fluoroalkyl, perfluoralkyl, oxo, amino, alkylamino,disubstituted amino, quaternary amino, amido, ester, alkylcarboxy,alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl,alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonato,phosphinato, acylamino (including alkylcarbonylamino, arylcarbonylamino,carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety. C₁₋₄ alkyls include,without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, andcyclobutyl. C₁₋₆ alkyls include, without limitation, methyl, ethyl,n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclobutyl, cyclopentyl, andcyclohexyl.

An example of a substituted alkyl is a heteroalkyl. By “heteroalkyl” ismeant a branched or unbranched alkyl, cycloalkyl, alkenyl, or alkynylgroup having from 1 to 7 or more carbon atoms in addition to 1, 2, 3 or4 heteroatoms independently selected from the group consisting of N, O,and S. By “C₁₋₇ heteroalkyl” is meant a branched or unbranched alkyl,alkenyl, or alkynyl group having from 1 to 7 carbon atoms in addition to1, 2, 3 or 4 heteroatoms independently selected from the groupconsisting of N, O, S, and P. Heteroalkyls can include, withoutlimitation, tertiary amines, secondary amines, ethers, thioethers,amides, thioamides, carbamates, thiocarbamates, hydrazones, imines,phosphodiesters, phosphoramidates, sulfonamides, and disulfides. Aheteroalkyl may optionally include monocyclic, bicyclic, or tricyclicrings, in which each ring desirably has three to six members. Theheteroalkyl group may be substituted or unsubstituted. Exemplarysubstituents include alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio,arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoralkyl,oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido,ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl, andureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety. Examples of C₁₋₇heteroalkyls include, without limitation, methoxymethyl and ethoxyethyl.

An alkenyl is a branched or unbranched hydrocarbon group containing oneor more double bonds. For example, by “C₂₋₆ alkenyl” or “C₂-C₆ alkenyl”is meant a branched or unbranched hydrocarbon group containing one ormore double bonds and having from 2 to 6 carbon atoms. An alkenyl mayoptionally include monocyclic or polycyclic rings, in which each ringdesirably has from three to six members. The alkenyl group may besubstituted or unsubstituted. Exemplary substituents include thosedescribed above for alkyl, and specifically include alkoxy, aryloxy,sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl,perfluoralkyl, amino, alkylamino, disubstituted amino, quaternary amino,alkylcarboxy, and carboxyl groups. C₂-₆ alkenyls include, withoutlimitation, vinyl, allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and2-methyl-2-propenyl.

An alkynyl is a branched or unbranched hydrocarbon group containing oneor more triple bonds. For example, by “C₂₋₆ alkynyl” or “C₂-C₆ alkynyl”is meant a branched or unbranched hydrocarbon group containing one ormore triple bonds and having from 2 to 6 carbon atoms. An alkynyl mayoptionally include monocyclic, bicyclic, or tricyclic rings, in whicheach ring desirably has five or six members. The alkynyl group may besubstituted or unsubstituted. Exemplary substituents those describedabove for alkyl, and specifically include alkoxy, aryloxy, sulfhydryl,alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino,alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, andcarboxyl groups. C₂₋₆ alkynyls include, without limitation, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

By “heterocyclyl,” “heterocyclic,” or “heterocycloalkyl” is meant astable monocyclic or polycyclic (including a bicyclic or a tricyclic)heterocyclic ring which is saturated, partially unsaturated orunsaturated (including heteroaryl or aromatic), and which consists of 2or more carbon atoms and 1, 2, 3 4 or more heteroatoms independentlyselected from N, O, and S and including any bicyclic or polycyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring, heteroaryl, cycloalkyl or heterocycloalkyl. In certainaspects, the heterocyclyl is a 3- to 15-membered ring system, a 3- to12- membered ring system, or a 3- to 9-membered ring system. By “C₂₋₆heterocyclyl” is meant a stable 5- to 7-membered monocyclic or 7- to14-membered bicyclic heterocyclic ring which is saturated, partiallyunsaturated or unsaturated (including heteroaryl or aromatic), and whichconsists of 2 to 6 carbon atoms and 1, 2, 3 or 4 heteroatomsindependently selected from N, O, and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring, heteroaryl, cycloalkyl or heterocycloalkyl. Theheterocyclyl or heteroaryl group may be substituted or unsubstituted.Exemplary substituents include substituted or unsubstituted alkyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy, sulfhydryl,alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino,alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, oxo,and carboxyl groups. The nitrogen and sulfur heteroatoms may optionallybe oxidized. The heterocyclic ring may be covalently attached via anyheteroatom or carbon atom which results in a stable structure, e.g., animidazolinyl ring may be linked at either of the ring-carbon atompositions or at the nitrogen atom. A nitrogen atom in the heterocyclecan be quaternized. Preferably when the total number of S and O atoms inthe heterocycle exceeds 1, then these heteroatoms are not adjacent toone another. Heterocycles include, without limitation, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, xanthenyl, β-lactam, γ-lactam and δ-lactam. Preferred 5to 10 membered heterocycles include, but are not limited to, pyridinyl,pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl,benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl,benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 memberedheterocycles include, without limitation, pyridinyl, quinolinyl,pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,and tetrazolyl. Preferred substituents include phenyl, methyl, ethyl,propyl, butyl, chloro, bromo, fluoro, iodo and oxo.

By “aryl” is meant an aromatic group having a ring system comprised ofcarbon atoms with conjugated π electrons (e.g., phenyl). A “C₆-C₁₂ aryl”or “C₆-C₁₀ aryl” is an aryl group that has from 6 to 12 carbon atoms or6 to 10 carbon atoms, respectively. Aryl groups may optionally includemonocyclic, bicyclic, or tricyclic rings, in which each ring desirablyhas five or six members. A bicyclic or tricyclic ring system can befused (e.g., naphthyl) or not (e.g., biphenyl). The aryl group may besubstituted or unsubstituted. Exemplary substituents include substitutedor unsubstituted alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl,alkylthio, arylthio, halide, fluoroalkyl, carboxyl, alkylcarboxy, amino,alkylamino, monosubstituted amino, disubstituted amino, and quaternaryamino groups. A preferred aryl group is phenyl.

By “aralkyl” is meant a substituted or unsubstituted alkyl that issubstituted by a substituted or unsubstituted aryl (including, forexample, (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl)).

By “C₇₋₁₄ aralkyl” is meant an alkyl substituted by an aryl group (e.g.,benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbonatoms.

By “C₃₋₁₀ heterocycloalkyl” is meant an alkyl substituted heterocyclicgroup having from 3 to 10 carbon atoms in addition to one or moreheteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl,3-tetrahydrofuranylmethyl, or 2-tetrahydrofuranylmethyl).

By “halide” or “halogen” is meant bromine, chlorine, iodine, orfluorine.

By “fluoroalkyl” is meant an alkyl group that is substituted with afluorine atom.

By “alkylcarboxy” is meant a chemical moiety with the formula —(R)—COOH,wherein R is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₂-₆heterocyclyl, C₆-₁₂ aryl, C₇₋ ₁₄ aralkyl, C₃-₁₀ heterocycloalkyl, orC₁₋₇ heteroalkyl.

By “alkylcarboxylate” is meant a chemical moiety with the formula—(R)—COOR”, wherein R is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇alkynyl, C₂-₆ heterocyclyl, C₆-₁₂ aryl, C₇₋ ₁₄ aralkyl, C₃-₁₀heterocycloalkyl, and C₁₋₇ heteroalkyl and R″ is selected from C₁₋₇alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₂-₆ heterocyclyl, C₆₋₁₂ aryl, C₇-₁₄aralkyl, C₃-₁₀ heterocycloalkyl, or C₁₋₇ heteroalkyl, each substitutedor unsubstituted.

By “alkylcarboxamide” is meant a chemical moiety with the formula—(R)—C(O)NR’R”, wherein R is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₂-₆ heterocyclyl, C₆₋₁₂ aryl, C₇-₁₄ aralkyl, C₃-₁₀heterocycloalkyl, or C₁₋₇ heteroalkyl, and R and R″ are eachindependently selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₂-₆heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ aralkyl, C₃-₁₀ heterocycloalkyl, or C₁₋₇heteroalkyl, or R′ and R″ together with the nitrogen to which they areattached may form a ring (for example, a 4- to 7-membered heterocyclicring), each substituted or unsubstituted.

By “alkoxy” is meant a chemical substituent of the formula —OR, whereinR is a substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, or substituted or unsubstituted alkynyl or R can be selectedfrom C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₂₋₆ heterocyclyl, C₆₋₁₂aryl, C₇-₁₄ aralkyl, C₃-₁₀ heterocycloalkyl, or C₁₋₇ heteroalkyl.

By “aryloxy” is meant a chemical substituent of the formula —OR, whereinR is a C₆₋₁₂ aryl group. By “alkylthio” is meant a chemical substituentof the formula —SR, wherein R is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₂-₆ heterocyclyl, C₆₋₁₂ aryl, C₇-₁₄ aralkyl, C₃₋ ₁₀heterocycloalkyl, or C₁₋₇ heteroalkyl.

By “arylthio” is meant a chemical substituent of the formula —SR,wherein R is a C₆₋₁₂ aryl group.

By “charged moiety” is meant a moiety which gains a proton atphysiological pH thereby becoming positively charged (e.g., ammonium,guanidinium, or amidinium) or a moiety that includes a net formalpositive charge without protonation (e.g., quaternary ammonium). Thecharged moiety may be either permanently charged or transiently charged.

By “therapeutically effective amount” or “effective amount” means anamount sufficient to produce a desired result, for example, thereduction or elimination of pain, cough, itch, or neurogenicinflammation in a patient (e.g., a human) suffering from a condition,disease, or illness that is caused wholly or in part by neurogenicinflammation (e.g. asthma, arthritis, colitis, contact dermatitis,diabetes, eczema, cystitis, chronic refractory cough, post-viral cough,gastritis, migraine headache, psoriasis, rhinitis, rosacea, or sunburn).

“Solvates” means solvent addition forms that contain eitherstoichiometric or nonstoichiometric amounts of solvent.

The compounds of the present invention, including salts of thecompounds, can exist in unsolvated forms as well as solvated forms,including hydrated forms and unhydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the present invention. Nonlimiting examples of hydrates includemonohydrates, dihydrates, hemihydrates, etc. In certain aspects, thecompound is a hemihydrate. Nonlimiting examples of solvates includeethanol solvates, acetone solvates, etc.

The compounds of the invention may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for usescontemplated by the present invention and are intended to be within thescope of the invention.

Compounds that can be used in the compositions, kits, and methods of theinvention include compounds having Formula (I), or a pharmaceuticallyacceptable salt thereof:

wherein:

-   Y⁻ is a pharmaceutically acceptable anion;-   n is 1, 2, 3, or 4;-   R^(A), R^(B), and R^(C) are each independently selected from H, D,    halogen, substituted or unsubstituted alkyl, substituted or    unsubstituted alkenyl, substituted or unsubstituted alkynyl,-   OR^(I), NR^(J)R^(K), NR^(L)C(O)R^(M), S(O)R^(N), S(O)₂R^(N),    SO₂R^(O)R^(P), SO₂NR^(Q)R^(R), SO₃R^(S), CO₂R^(T), C(O)R^(U), and    C(O)NR^(V)R^(W);-   each of R^(I), R^(J), R^(K), R^(L), R^(M), R^(N), R^(O), R^(P),    R^(Q), R^(R), R^(S), R^(T), R^(U), R^(V), and R^(W) is independently    selected from H, D, substituted or unsubstituted alkyl, substituted    or unsubstituted alkenyl, and substituted or unsubstituted alkynyl;-   X¹ is selected from —CR^(X)R^(Y)—, —NR^(Z)C(O)—,    —NR^(Z)C(O)CR^(X)R^(Y)—,—OC(O)—, —SC(O)—, —C(O)NR^(1A)—, —C(O)O—,    —C(O)—, —(O)CS—, —NR^(1A)S(O)—, —S(O)NR^(1A)—, —NR^(1A)C(O)NR^(1A)—,    —S(O)— and —S(O)₂—;-   each of R^(X), R^(Y), R^(Z), and R^(1A) is independently selected    from H, D, substituted or unsubstituted alkyl, substituted or    unsubstituted alkenyl, and substituted or unsubstituted alkynyl;-   each of R^(D) and R^(E) is independently selected from H, D,    substituted or unsubstituted alkyl, substituted or unsubstituted    alkenyl, substituted or unsubstituted alkynyl, and substituted or    unsubstituted cycloalkyl; or R^(D) and R^(E) together with the    carbon to which they are attached form a substituted or    unsubstituted C₃-C₆ cycloalkyl or a substituted or unsubstituted    heterocyclic (for example, a 5- to 7-membered heterocyclic ring);-   R^(H) is a substituted or unsubstituted alkyl, substituted or    unsubstituted aralkyl, or, substituted or unsubstituted    heteroaralkyl; and-   R^(1B) is a substituted or unsubstituted aryl or substituted or    unsubstituted heteroaryl, preferably substituted or unsubstituted    phenyl.

In a preferred embodiment, R^(H) is substituted or unsubstituted alkyl.

In an additional preferred embodiment, R^(H) is alkylcarboxylate.

In further preferred embodiments, R^(H) is alkylcarboxamide.

In yet additional aspects, R^(H) is a substituted or unsubstitutedaralkyl or heteroaralkyl.

In a preferred embodiment, R^(H) is independently selected from asubstituted or unsubstituted C₅₋₁₀ arylmethyl or a substituted orunsubstituted C₅₋₁₀ heteroarylmethyl.

In a further preferred embodiment, R^(H) is independently selected froma substituted or unsubstituted C₆₋₁₀ arylmethyl or a substituted orunsubstituted 5- to 10-membered heteroarylmethyl.

In some embodiments, R^(H) is a substituted C₅₋₁₀ arylalkyl or asubstituted C₅₋₁₀ heteroarylalkyl optionally substituted with C₁₋₆alkyl, C₁₋₆ heteroalkyl, carbocyclyl, substituted carbocyclyl,heterocarbocyclyl, substituted heterocarbocyclyl, phenyl, substitutedphenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,carboxamide, hydroxyl, ether, amide, ester, sulfonamide, sulfone, amino,amino alkyl, urea, nitrile, or halogen. In a preferred embodiment, theC₁₋₆ alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. In apreferred embodiment, the C₁₋₆ heteroalkyl is selected from —O—methyl,—O—ethyl, —O—propyl, —O—isopropyl, —O—butyl, —O—isobutyl, —O—cyclohexyl,—O—cyclopentyl, and -ethyl-O-methyl. In a preferred embodiment, thecarbocyclyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. In a preferred embodiment, the heterocarbocyclyl is selectedfrom aziridinyl, azetidinyl, furanyl, pyrrolidinyl, pyranyl,piperidinyl, piperazinyl, azepinyl, and diazapinyl.

In yet another preferred embodiment, R^(H) is a substituted orunsubstituted C₆₋₁₀ aralkyl or a substituted or unsubstituted 5- to10-membered heteroarylalkyl. In certain aspects, R^(H) is anunsubstituted C₆₋₁₀ arylmethyl or an unsubstituted 5- to 10-memberedheteroarylmethyl, each optionally substituted with a substituted orunsubstituted C₁-C₆ alkyl, halo, nitrile, hydroxyl, and alkoxy. In yetadditional aspects, R^(H) is a C₆₋₁₀ aryl or a 5- to 10-memberedheteroaryl, each optionally substituted with a substituted orunsubstituted C₁-C₆ alkyl, halo, nitrile, and OR^(2B), wherein R^(2B) ishydrogen or substituted or unsubstituted C₁-C₆ alkyl. In a furtherpreferred embodiment, R^(H) is an unsubstituted benzyl. In additionalembodiments, R^(H) is benzyl substituted with a substituent selectedfrom the group consisting of substituted or unsubstituted C₁-C₆ alkyl,halo, nitrile, hydroxyl, and alkoxy. In additional aspects, R^(H) isbenzyl is substituted with a substituent selected from the groupconsisting of substituted or unsubstituted C₁-C₆ alkyl, halo, nitrile,and OR^(2B), wherein R^(2B) is hydrogen or substituted, andunsubstituted C₁-C₆ alkyl. In yet additional embodiments, R^(H) isbenzyl substituted with an unsubstituted C₁-C₆ alkyl, halo, nitrile,hydroxyl, or alkoxy. In further aspects, R^(H) is benzyl substitutedwith a substituent selected from the group consisting of unsubstitutedC₁-C₆ alkyl, halo, nitrile, and OR^(2B), wherein R^(2B) is hydrogen orsubstituted or unsubstituted C₁-C₆ alkyl.

In yet further aspects, R_(H) is selected from the -CH₂Z groups shown inTables 1 to 3.

In a preferred embodiment, X¹ is —NHC(O)— or —C(O)NH—. In anotherpreferred embodiment, X¹ is —NHC(O)—.

In preferred embodiments, R^(A), R^(B), and R^(C) are each independentlyselected from H, D, halogen, substituted or unsubstituted C₁₋₄ alkyl,and NR^(J)R^(K); and each of R^(J) and R^(K) is independently selectedfrom H and substituted or unsubstituted C₁₋₄ alkyl.

In a preferred embodiment, each of R^(A) and R^(B) is CH₃, and R^(C) isH, CH₃, halogen, nitrile, methoxy, or ethoxy.

In yet additional preferred aspects, R^(A), R^(B), and R^(C) areindependently selected from H, D, halogen, OR^(I), substituted orunsubstituted C₁-C₄ alkyl, and NR^(J)R^(K); wherein each of R^(I), R^(J)and R^(K) is independently selected from H and substituted orunsubstituted C₁-C₄ alkyl. In a preferred embodiment, each of R^(A) andR^(B) is CH₃, and R^(C) is selected from the group consisting of H, CH₃,halogen, nitrile (cyano), methoxy, and ethoxy. In further preferredembodiments, each of R^(A) and R^(B) is CH₃, and R^(C) is selected fromthe group consisting of H, CH₃, fluoro, chloro, nitrile, methoxy, andethoxy. In additional preferred embodiments, each of R^(A) and R^(B) areCH₃ and R^(C) is hydrogen.

In certain other embodiments, R^(D) is C₁₋₄ alkyl optionally substitutedwith a substituent selected from the group consisting of halogen,oxygen, C₃₋₈ cycloalkyl, aryl, or heteroaryl, and/or R^(E) is H or C₁₋₄alkyl optionally substituted with a substituent selected from the groupconsisting of halogen, oxygen, C₃₋₈ cycloalkyl, aryl, or heteroaryl.

In preferred embodiments each of R^(D) and R^(E) is independentlyselected from H, D, CH₃, CH₂CH₃, (CH₂)₂CH₃, and (CH₂)₃CH₃. In a morepreferred embodiment, R^(E) is hydrogen and R^(D) is CH₃, CH₂CH₃,(CH₂)₂CH₃, or (CH₂)₃CH₃. In certain, other preferred embodiments R^(D)and R^(E) together form a substituted or unsubstituted C₃-C₆ cycloalkyl.

In certain preferred embodiments, R^(D) and R^(E) are both hydrogen. Inyet additional preferred embodiments, R^(D) is hydrogen and R^(E) is analkyl, for example, a C₁-C₆ alkyl or a C₁₋ C₄ alkyl including, but notlimited to, methyl, ethyl, propyl and butyl. In certain additionalpreferred embodiments, R^(D) and R^(E) are taken together with thecarbon to which they are attached to form a C₃-C₆ cycloalkyl including,but not limited to, cyclopropyl or cyclobutyl.

In certain preferred embodiments, n is 0. In other preferred aspects, nis 1. In other preferred aspects, n is 2. In yet further preferredaspects, n is 3. In further aspects, n is 4.

In certain aspects, R^(1B) is unsubstituted phenyl.

In yet additional aspects, R^(1B) is substituted or unsubstitutedpyridinyl; preferably, unsubstituted pyridinyl.

In some embodiments Y⁻ is a halide anion, a carboxylate, or a sulfonate.Y⁻ can, for example, be a halide ion, a substituted or unsubstitutedalkylsulfonate, a substituted or unsubstituted aryl sulfonate, asubstituted or unsubstitued alkyl or aliphatic carboxylate, asubstituted or unsubstituted aryl carboxylate, or a substituted orunsubstituted heterocyclyl carboxylate.

In certain embodiments, Y- is selected from the group consisting oftrifluoroacetate, sulfate, phosphate, acetate, fumarate, formate,carbonate, maleate, citrate, pyruvate, succinate, oxalate, a sulfonate,(for example, methanesulfonate, trifluoromethanesulfonate,toluenesulfonate such as p-toluenesulfonate, benzenesulfonate,ethanesulfonate, camphorsulfonate, 2-mesitylenesulfonate, ornaphthalenesulfonate such as 2-naphthalenesulfonate), bisulfate,malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate,adipate, formate, glycolate, L-lactate, D-lactate, aspartate, malate,L-tartrate, D-tartrate, stearate, 2-furoate, 3-furoate, napadisylate(naphthalene-1,5-disulfonate or naphthalene-1-(sulfonicacid)-5-sulfonate), edisylate (ethane-1,2-disulfonate orethane-1-(sulfonic acid)-2-sulfonate), isethionate(2-hydroxyethylsulfonate), D-mandelate, L-mandelate, propionate,tartarate, phthalate, hydrochlorate, hydrobromate, and nitrate. In oneembodiment, Y⁻ is a halide anion.

In a preferred embodiment, the anion is selected from the halide ionsbromide, chloride, or iodide.

Each preferred group stated above can be taken in combination with one,any or all other preferred groups.

In a preferred embodiment, the present invention relates to compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, whereinR^(1B) is an optionally substituted aryl or optionally substitutedheteroaryl selected from one of the following:

In certain preferred aspects, R^(1B) is substituted or unsubstitutedphenyl.

In certain additional aspects, the compound has the Formula (II):

wherein:

-   Y⁻ is a pharmaceutically acceptable anion;-   q is 0, 1, 2, or 3;-   R^(D) is hydrogen, methyl, or ethyl; and-   R^(1B) is as defined above.

In some embodiments, the compound has the Formula (II), wherein Y⁻ is ahalide anion, a carboxylate, or a sulfonate. Y⁻ can, for example, be ahalide ion, a substituted or unsubstituted alkylsulfonate, a substitutedor unsubstituted arylsulfonate, a substituted or unsubstitued alkyl oraliphatic carboxylate, a substituted or unsubstituted aryl carboxylate,or a substituted or unsubstituted heterocyclyl carboxylate.

In certain embodiments, the compound has the Formula (II), wherein Y⁻ isselected from the group consisting of trifluoroacetate, sulfate,phosphate, acetate, fumarate, formate, carbonate, maleate, citrate,pyruvate, succinate, oxalate, a sulfonate, (for example,methanesulfonate, trifluoromethanesulfonate, toluenesulfonate such asp-toluenesulfonate, benzenesulfonate, ethanesulfonate, camphorsulfonate,2-mesitylenesulfonate, or naphthalenesulfonate such as2-naphthalenesulfonate), bisulfate, malonate, xinafoate, ascorbate,oleate, nicotinate, saccharinate, adipate, formate, glycolate,L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate,stearate, 2-furoate, 3-furoate, napadisylate(naphthalene-1,5-disulfonate or naphthalene-1-(sulfonicacid)-5-sulfonate), edisylate (ethane-1,2-disulfonate orethane-1-(sulfonic acid)-2-sulfonate), isethionate(2-hydroxyethylsulfonate), D-mandelate, L-mandelate, propionate,tartarate, phthalate, hydrochlorate, hydrobromate, and nitrate.

In one embodiment, the compound has the Formula (II) and Y⁻ is halideanion. In a preferred embodiment, Y⁻ is selected from the halide ionsbromide, chloride, or iodide.

In certain preferred embodiments, q is 0. In other preferred aspects, qis 1. In other preferred aspects, q is 2. In yet further preferredaspects, q is 3.

In yet additional preferred aspects, the compound has the Formula (II)and R^(D) is hydrogen.

In further aspects, the compound has the Formula (II) and R^(D) ismethyl.

In yet other aspects, the compound has the Formula (II) and R^(D) isethyl.

In yet further aspects, the compound has the Formula (II), q is 0 andR^(D) is hydrogen.

In additional preferred aspects, the compound has the Formula (II), q is1 and R^(D) is hydrogen.

In further preferred aspects, the compound has the Formula (II) and q is2, and R^(D) is hydrogen.

In additional aspects, the compound has the Formula (II), q is 3, andR^(D) is hydrogen.

In yet additional preferred embodiments, the compound has the Formula(II), and q is 0 and R^(D) is methyl.

In additional preferred aspects, the compound has the Formula (II), q is1 and R^(D) is methyl.

In further preferred aspects, the compound has the Formula (II), q is 2and R^(D) is methyl.

In additional aspects, the compound has the Formula (II), q is 3 andR^(D) is methyl.

In further preferred embodiments, the compound has the Formula (II), qis 0 and R^(D) is ethyl.

In additional preferred aspects, the compound has the Formula (II), q is1 and R^(D) is ethyl.

In further preferred aspects, the compound has the Formula (II), q is 2and R^(D) is ethyl.

In additional aspects, the compound has the Formula (II), q is 3 andR^(D) is ethyl.

In yet an additional aspect, the compound is selected from the Tablebelow, or a pharmaceutically acceptable salt thereof, wherein Y⁻ is apharmaceutically acceptable anion.

Representative compounds according to the invention and theirenantiomers and pharmaceutically acceptable salts thereof are thoseselected from Table C below, wherein Y⁻ is a pharmaceutically acceptableanion, as defined above, and Z is either an aryl or a heteroarylstructure selected from one of the structures in Table 1, or asubstituted aryl or substituted heteroaryl structure selected from oneof the structures in Tables 2-3.

TABLE C Representative Compounds of the Invention No. Structure No.Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

TABLE 1 Representative Z Structures No. Structure No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32 —H 33 —Me 34 —Et 35 —CH₂COOMe 36 —CH₂COOEt 37 —CH₂CONH₂ 38 —CH₂CONHMe39 —CH₂CONHEt 40 —CH₂CONHPr 41 —CH₂CON(CH₃)₂ 42 CH₂CON(C₂H₅)₂ 43 —COOMe44 —COOEt 45 —CONH₂ 46 —CONHMe 47 —CONHEt 48 —CONHPr 49 —CON(CH₃)₂ 50—CON(C₂H₅)₂ 51 —H 52 —COOPh 53

54

55

56

57 —(CH₂)₂COOMe 58 —(CH₂)₃COOMe 59 —(CH₂)₂COOEt 60 —(CH₂)₃COOEt 61—(CH₂)₂COOPh 62 —(CH₂)₃COOPh 63 —CH₂COOPh 64

65

66

67

TABLE 2 Representative Z Structures No. Structure No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

TABLE 3 Representative Z Structures No. Structure No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

Preferred compounds according to the invention and their enantiomers andpharmaceutically acceptable salts thereof are represented by Formula(IIIa),

wherein the preferred substituent combinations R^(C), R^(D), and Z areas defined in Table 4a, and Y⁻ is a pharmaceutically acceptable anion asdefined above, and q is 0, 1, 2, or 3. In certain preferred embodiments,the compound is selected from Table 4a wherein q is 0. In otherpreferred aspects, the compound is selected from Table 4a wherein qis 1. In other preferred aspects, the compound is selected from Table 4awherein q is 2. In yet further preferred aspects, the compound isselected from Table 4a wherein q is 3. The compounds can be madeaccording to the methods generally described below.

TABLE 4a Preferred Combinations of R^(C), R^(D), and Z Substituentsaccording to Formula (III) Combination Number R^(C) R^(D) Z 1 H H

2 Cl H

3 CH₃ H

4 H CH₃

5 Cl CH₃

6 CH₃ CH₃

7 H CH₂CH₃

8 Cl CH₂CH₃

9 CH₃ CH₂CH₃

10 H (CH₂)₂CH₃

11 Cl (CH₂)₂CH₃

12 CH₃ (CH₂)₂CH₃

13 H H

14 Cl H

15 CH₃ H

16 H CH₃

17 Cl CH₃

18 CH₃ CH₃

19 H CH₂CH₃

20 Cl CH₂CH₃

21 CH₃ CH₂CH₃

22 H (CH₂)₂CH₃

23 Cl (CH₂)₂CH₃

24 CH₃ (CH₂)₂CH₃

25 H H

26 Cl H

27 CH₃ H

28 H CH₃

29 Cl CH₃

30 CH₃ CH₃

31 H CH₂CH₃

32 Cl CH₂CH₃

33 CH₃ CH₂CH₃

34 H (CH₂)₂CH₃

35 Cl (CH₂)₂CH₃

36 CH₃ (CH₂)₂CH₃

37 H H

38 Cl H

39 CH₃ H

40 H CH₃

41 Cl CH₃

42 CH₃ CH₃

43 H CH₂CH₃

44 Cl CH₂CH₃

45 CH₃ CH₂CH₃

46 H (CH₂)₂CH₃

47 Cl (CH₂)₂CH₃

48 CH₃ (CH₂)₂CH₃

49 H H

50 Cl H

51 CH₃ H

52 H CH₃

53 Cl CH₃

54 CH₃ CH₃

55 H CH₂CH₃

56 Cl CH₂CH₃

57 CH₃ CH₂CH₃

58 H (CH₂)₂CH₃

59 Cl (CH₂)₂CH₃

60 CH₃ (CH₂)₂CH₃

61 H H

62 Cl H

63 CH₃ H

64 H CH₃

65 Cl CH₃

66 CH₃ CH₃

67 H CH₂CH₃

68 Cl CH₂CH₃

69 CH₃ CH₂CH₃

70 H (CH₂)₂CH₃

71 Cl (CH₂)₂CH₃

72 CH₃ (CH₂)₂CH₃

73 H H

74 Cl H

75 CH₃ H

76 H CH₃

77 Cl CH₃

78 CH₃ CH₃

79 H CH₂CH₃

80 Cl CH₂CH₃

81 CH₃ CH₂CH₃

82 H (CH₂)₂CH₃

83 Cl (CH₂)₂CH₃

84 CH₃ (CH₂)₂CH₃

85 H H

86 Cl H

87 CH₃ H

88 H CH₃

89 Cl CH₃

90 CH₃ CH₃

91 H CH₂CH₃

92 Cl CH₂CH₃

93 CH₃ CH₂CH₃

94 H (CH₂)₂CH₃

95 Cl (CH₂)₂CH₃

96 CH₃ (CH₂)₂CH₃

97 H H

98 Cl H

99 CH₃ H

100 H CH₃

101 Cl CH₃

102 CH₃ CH₃

103 H CH₂CH₃

104 Cl CH₂CH₃

105 CH₃ CH₂CH₃

106 H (CH₂)₂CH₃

107 Cl (CH₂)₂CH₃

108 CH₃ (CH₂)₂CH₃

109 H H

110 Cl H

111 CH₃ H

112 H CH₃

113 Cl CH₃

114 CH₃ CH₃

115 H CH₂CH₃

116 Cl CH₂CH₃

117 CH₃ CH₂CH₃

118 H (CH₂)₂CH₃

119 Cl (CH₂)₂CH₃

120 CH₃ (CH₂)₂CH₃

121 H H

122 Cl H

123 CH₃ H

124 H CH₃

125 Cl CH₃

126 CH₃ CH₃

127 H CH₂CH₃

128 Cl CH₂CH₃

129 CH₃ CH₂CH₃

130 H (CH₂)₂CH₃

131 Cl (CH₂)₂CH₃

132 CH₃ (CH₂)₂CH₃

133 H H

134 Cl H

135 CH₃ H

136 H CH₃

137 Cl CH₃

138 CH₃ CH₃

139 H CH₂CH₃

140 Cl CH₂CH₃

141 CH₃ CH₂CH₃

142 H (CH₂)₂CH₃

143 Cl (CH₂)₂CH₃

144 CH₃ (CH₂)₂CH₃

145 H H

146 Cl H

147 CH₃ H

148 H CH₃

149 Cl CH₃

150 CH₃ CH₃

151 H CH₂CH₃

152 Cl CH₂CH₃

153 CH₃ CH₂CH₃

154 H (CH₂)₂CH₃

155 Cl (CH₂)₂CH₃

156 CH₃ (CH₂)₂CH₃

157 H H

158 Cl H

159 CH₃ H

160 H CH₃

161 Cl CH₃

162 CH₃ CH₃

163 H CH₂CH₃

164 Cl CH₂CH₃

165 CH₃ CH₂CH₃

166 H (CH₂)₂CH₃

167 Cl (CH₂)₂CH₃

168 CH₃ (CH₂)₂CH₃

169 H H

170 Cl H

171 CH₃ H

172 H CH₃

173 Cl CH₃

174 CH₃ CH₃

175 H CH₂CH₃

176 Cl CH₂CH₃

177 CH₃ CH₂CH₃

178 H (CH₂)₂CH₃

179 Cl (CH₂)₂CH₃

180 CH₃ (CH₂)₂CH₃

181 H H

182 Cl H

183 CH₃ H

184 H CH₃

185 Cl CH₃

186 CH₃ CH₃

187 H CH₂CH₃

188 Cl CH₂CH₃

189 CH₃ CH₂CH₃

190 H (CH₂)₂CH₃

191 Cl (CH₂)₂CH₃

192 CH₃ (CH₂)₂CH₃

193 H H

194 Cl H

195 CH₃ H

196 H CH₃

197 Cl CH₃

198 CH₃ CH₃

199 H CH₂CH₃

200 Cl CH₂CH₃

201 CH₃ CH₂CH₃

202 H (CH₂)₂CH₃

203 Cl (CH₂)₂CH₃

204 CH₃ (CH₂)₂CH₃

205 H H

206 Cl H

207 CH₃ H

208 H CH₃

209 Cl CH₃

210 CH₃ CH₃

211 H CH₂CH₃

212 Cl CH₂CH₃

213 CH₃ CH₂CH₃

214 H (CH₂)₂CH₃

215 Cl (CH₂)₂CH₃

216 CH₃ (CH₂)₂CH₃

217 H H

218 Cl H

219 CH₃ H

220 H CH₃

221 Cl CH₃

222 CH₃ CH₃

223 H CH₂CH₃

224 Cl CH₂CH₃

225 CH₃ CH₂CH₃

226 H (CH₂)₂CH₃

227 Cl (CH₂)₂CH₃

228 CH₃ (CH₂)₂CH₃

229 H H

230 Cl H

231 CH₃ H

232 H CH₃

233 Cl CH₃

234 CH₃ CH₃

235 H CH₂CH₃

236 Cl CH₂CH₃

237 CH₃ CH₂CH₃

238 H (CH₂)₂CH₃

239 Cl (CH₂)₂CH₃

240 CH₃ (CH₂)₂CH₃

241 H H

242 Cl H

243 CH₃ H

244 H CH₃

245 Cl CH₃

246 CH₃ CH₃

247 H CH₂CH₃

248 Cl CH₂CH₃

249 CH₃ CH₂CH₃

250 H (CH₂)₂CH₃

251 Cl (CH₂)₂CH₃

252 CH₃ (CH₂)₂CH₃

253 H H

254 Cl H

255 CH₃ H

256 H CH₃

257 Cl CH₃

258 CH₃ CH₃

259 H CH₂CH₃

260 Cl CH₂CH₃

261 CH₃ CH₂CH₃

262 H (CH₂)₂CH₃

263 Cl (CH₂)₂CH₃

264 CH₃ (CH₂)₂CH₃

265 H H

266 Cl H

267 CH₃ H

268 H CH₃

269 Cl CH₃

270 CH₃ CH₃

271 H CH₂CH₃

272 Cl CH₂CH₃

273 CH₃ CH₂CH₃

274 H (CH₂)₂CH₃

275 Cl (CH₂)₂CH₃

276 CH₃ (CH₂)₂CH₃

277 H H

278 Cl H

279 CH₃ H

280 H CH₃

281 Cl CH₃

282 CH₃ CH₃

283 H CH₂CH₃

284 Cl CH₂CH₃

285 CH₃ CH₂CH₃

286 H (CH₂)₂CH₃

287 Cl (CH₂)₂CH₃

288 CH₃ (CH₂)₂CH₃

289 H H

290 Cl H

291 CH₃ H

292 H CH₃

293 Cl CH₃

294 CH₃ CH₃

295 H CH₂CH₃

296 Cl CH₂CH₃

297 CH₃ CH₂CH₃

298 H (CH₂)₂CH₃

299 Cl (CH₂)₂CH₃

300 CH₃ (CH₂)₂CH₃

301 H H

302 Cl H

303 CH₃ H

304 H CH₃

305 Cl CH₃

306 CH₃ CH₃

307 H CH₂CH₃

308 Cl CH₂CH₃

309 CH₃ CH₂CH₃

310 H (CH₂)₂CH₃

311 Cl (CH₂)₂CH₃

312 CH₃ (CH₂)₂CH₃

313 H H

314 Cl H

315 CH₃ H

316 H CH₃

317 Cl CH₃

318 CH₃ CH₃

319 H CH₂CH₃

320 Cl CH₂CH₃

321 CH₃ CH₂CH₃

322 H (CH₂)₂CH₃

323 Cl (CH₂)₂CH₃

324 CH₃ (CH₂)₂CH₃

325 H H

326 Cl H

327 CH₃ H

328 H CH₃

329 Cl CH₃

330 CH₃ CH₃

331 H CH₂CH₃

332 Cl CH₂CH₃

333 CH₃ CH₂CH₃

334 H (CH₂)₂CH₃

335 Cl (CH₂)₂CH₃

336 CH₃ (CH₂)₂CH₃

337 H H

338 Cl H

339 CH₃ H

340 H CH₃

341 Cl CH₃

342 CH₃ CH₃

343 H CH₂CH₃

344 Cl CH₂CH₃

345 CH₃ CH₂CH₃

346 H (CH₂)₂CH₃

347 Cl (CH₂)₂CH₃

348 CH₃ (CH₂)₂CH₃

349 H H

350 Cl H

351 CH₃ H

352 H CH₃

353 Cl CH₃

354 CH₃ CH₃

355 H CH₂CH₃

356 Cl CH₂CH₃

357 CH₃ CH₂CH₃

358 H (CH₂)₂CH₃

359 Cl (CH₂)₂CH₃

360 CH₃ (CH₂)₂CH₃

361 H H

362 Cl H

363 CH₃ H

364 H CH₃

365 Cl CH₃

366 CH₃ CH₃

367 H CH₂CH₃

368 Cl CH₂CH₃

369 CH₃ CH₂CH₃

370 H (CH₂)₂CH₃

371 Cl (CH₂)₂CH₃

372 CH₃ (CH₂)₂CH₃

373 H H CO₂Me 374 H Et CO₂Me 375 H H CO₂Et 376 H Et CO₂Et 377 H HCH₂CO₂Me 378 H Et CH₂CO₂Me 379 H H CH₂CO₂Et 380 H Et CH₂CO₂Et 381 H H(CH₂)₂CO₂Me 382 H Et (CH₂)₂CO₂Me 383 H H (CH₂)₃CO₂Me 384 H Et(CH₂)₃CO₂Me 385 H H (CH₂)₃CO₂Et 386 H Et (CH₂)₃CO₂Et 387 H H (CH₂)₃CO₂Ph388 H Et (CH₂)₃CO₂Ph

Preferred compounds according to the invention and their enantiomers andpharmaceutically acceptable salts thereof are represented by Formula(IIIb),

wherein the preferred substituent combinations R^(C), R^(D), and Z areas defined in Table 4b, and Y⁻ is a pharmaceutically acceptable anion asdefined above, and q is 0, 1, 2, or 3. In certain preferred embodiments,the compound is selected from Table 4b wherein q is 0. In otherpreferred aspects, the compound is selected from Table 4b wherein qis 1. In other preferred aspects, the compound is selected from Table 4bwherein q is 2. In yet further preferred aspects, the compound isselected from Table 4b wherein q is 3. The compounds can be madeaccording to the methods generally described below.

TABLE 4b Preferred Combinations of R^(C), R^(D), and Z Substituentsaccording to Formula (IIIb) . Combination Number R^(C) R^(D) Z 1 H H

2 Cl H

3 CH₃ H

4 H CH₃

5 Cl CH₃

6 CH₃ CH₃

7 H CH₂CH₃

8 Cl CH₂CH₃

9 CH₃ CH₂CH₃

10 H (CH₂)₂CH₃

11 Cl (CH₂)₂CH₃

12 CH₃ (CH₂)₂CH₃

13 H H

14 Cl H

15 CH₃ H

16 H CH₃

17 Cl CH₃

18 CH₃ CH₃

19 H CH₂CH₃

20 Cl CH₂CH₃

21 CH₃ CH₂CH₃

22 H (CH₂)₂CH₃

23 Cl (CH₂)₂CH₃

24 CH₃ (CH₂)₂CH₃

25 H H

26 Cl H

27 CH₃ H

28 H CH₃

29 Cl CH₃

30 CH₃ CH₃

31 H CH₂CH₃

32 Cl CH₂CH₃

33 CH₃ CH₂CH₃

34 H (CH₂)₂CH₃

35 Cl (CH₂)₂CH₃

36 CH₃ (CH₂)₂CH₃

37 H H

38 Cl H

39 CH₃ H

40 H CH₃

41 Cl CH₃

42 CH₃ CH₃

43 H CH₂CH₃

44 Cl CH₂CH₃

45 CH₃ CH₂CH₃

46 H (CH₂)₂CH₃

47 Cl (CH₂)₂CH₃

48 CH₃ (CH₂)₂CH₃

49 H H

50 Cl H

51 CH₃ H

52 H CH₃

53 Cl CH₃

54 CH₃ CH₃

55 H CH₂CH₃

56 Cl CH₂CH₃

57 CH₃ CH₂CH₃

58 H (CH₂)₂CH₃

59 Cl (CH₂)₂CH₃

60 CH₃ (CH₂)₂CH₃

61 H H

62 Cl H

63 CH₃ H

64 H CH₃

65 Cl CH₃

66 CH₃ CH₃

67 H CH₂CH₃

68 Cl CH₂CH₃

69 CH₃ CH₂CH₃

70 H (CH₂)₂CH₃

71 Cl (CH₂)₂CH₃

72 CH₃ (CH₂)₂CH₃

73 H H

74 Cl H

75 CH₃ H

76 H CH₃

77 Cl CH₃

78 CH₃ CH₃

79 H CH₂CH₃

80 Cl CH₂CH₃

81 CH₃ CH₂CH₃

82 H (CH₂)₂CH₃

83 Cl (CH₂)₂CH₃

84 CH₃ (CH₂)₂CH₃

85 H H

86 Cl H

87 CH₃ H

88 H CH₃

89 Cl CH₃

90 CH₃ CH₃

91 H CH₂CH₃

92 Cl CH₂CH₃

93 CH₃ CH₂CH₃

94 H (CH₂)₂CH₃

95 Cl (CH₂)₂CH₃

96 CH₃ (CH₂)₂CH₃

97 H H

98 Cl H

99 CH₃ H

100 H CH₃

101 C1 CH₃

102 CH₃ CH₃

103 H CH₂CH₃

104 Cl CH₂CH₃

105 CH₃ CH₂CH₃

106 H (CH₂)₂CH₃

107 Cl (CH₂)₂CH₃

108 CH₃ (CH₂)₂CH₃

109 H H

110 Cl H

111 CH₃ H

112 H CH₃

113 Cl CH₃

114 CH₃ CH₃

115 H CH₂CH₃

116 Cl CH₂CH₃

117 CH₃ CH₂CH₃

118 H (CH₂)₂CH₃

119 Cl (CH₂)₂CH₃

120 CH₃ (CH₂)₂CH₃

121 H H

122 Cl H

123 CH₃ H

124 H CH₃

125 Cl CH₃

126 CH₃ CH₃

127 H CH₂CH₃

128 Cl CH₂CH₃

129 CH₃ CH₂CH₃

130 H (CH₂)₂CH₃

131 Cl (CH₂)₂CH₃

132 CH₃ (CH₂)₂CH₃

133 H H

134 Cl H

135 CH₃ H

136 H CH₃

137 Cl CH₃

138 CH₃ CH₃

139 H CH₂CH₃

140 Cl CH₂CH₃

141 CH₃ CH₂CH₃

142 H (CH₂)₂CH₃

143 Cl (CH₂)₂CH₃

144 CH₃ (CH₂)₂CH₃

145 H H

146 Cl H

147 CH₃ H

148 H CH₃

149 Cl CH₃

150 CH₃ CH₃

151 H CH₂CH₃

152 Cl CH₂CH₃

153 CH₃ CH₂CH₃

154 H (CH₂)₂CH₃

155 Cl (CH₂)₂CH₃

156 CH₃ (CH₂)₂CH₃

157 H H

158 Cl H

159 CH₃ H

160 H CH₃

161 Cl CH₃

162 CH₃ CH₃

163 H CH₂CH₃

164 Cl CH₂CH₃

165 CH₃ CH₂CH₃

166 H (CH₂)₂CH₃

167 Cl (CH₂)₂CH₃

168 CH₃ (CH₂)₂CH₃

169 H H

170 Cl H

171 CH₃ H

172 H CH₃

173 Cl CH₃

174 CH₃ CH₃

175 H CH₂CH₃

176 Cl CH₂CH₃

177 CH₃ CH₂CH₃

178 H (CH₂)₂CH₃

179 Cl (CH₂)₂CH₃

180 CH₃ (CH₂)₂CH₃

181 H H

182 Cl H

183 CH₃ H

184 H CH₃

185 Cl CH₃

186 CH₃ CH₃

187 H CH₂CH₃

188 Cl CH₂CH₃

189 CH₃ CH₂CH₃

190 H (CH₂)₂CH₃

191 Cl (CH₂)₂CH₃

192 CH₃ (CH₂)₂CH₃

193 H H

194 Cl H

195 CH₃ H

196 H CH₃

197 Cl CH₃

198 CH₃ CH₃

199 H CH₂CH₃

200 Cl CH₂CH₃

201 CH₃ CH₂CH₃

202 H (CH₂)₂CH₃

203 Cl (CH₂)₂CH₃

204 CH₃ (CH₂)₂CH₃

205 H H

206 Cl H

207 CH₃ H

208 H CH₃

209 Cl CH₃

210 CH₃ CH₃

211 H CH₂CH₃

212 Cl CH₂CH₃

213 CH₃ CH₂CH₃

214 H (CH₂)₂CH₃

215 Cl (CH₂)₂CH₃

216 CH₃ (CH₂)₂CH₃

217 H H

218 Cl H

219 CH₃ H

220 H CH₃

221 Cl CH₃

222 CH₃ CH₃

223 H CH₂CH₃

224 Cl CH₂CH₃

225 CH₃ CH₂CH₃

226 H (CH₂)₂CH₃

227 Cl (CH₂)₂CH₃

228 CH₃ (CH₂)₂CH₃

229 H H

230 Cl H

231 CH₃ H

232 H CH₃

233 Cl CH₃

234 CH₃ CH₃

235 H CH₂CH₃

236 Cl CH₂CH₃

237 CH₃ CH₂CH₃

238 H (CH₂)₂CH₃

239 Cl (CH₂)₂CH₃

240 CH₃ (CH₂)₂CH₃

241 H H

242 Cl H

243 CH₃ H

244 H CH₃

245 Cl CH₃

246 CH₃ CH₃

247 H CH₂CH₃

248 Cl CH₂CH₃

249 CH₃ CH₂CH₃

250 H (CH₂)₂CH₃

251 Cl (CH₂)₂CH₃

252 CH₃ (CH₂)₂CH₃

253 H H

254 Cl H

255 CH₃ H

256 H CH₃

257 Cl CH₃

258 CH₃ CH₃

259 H CH₂CH₃

260 Cl CH₂CH₃

261 CH₃ CH₂CH₃

262 H (CH₂)₂CH₃

263 Cl (CH₂)₂CH₃

264 CH₃ (CH₂)₂CH₃

265 H H

266 Cl H

267 CH₃ H

268 H CH₃

269 Cl CH₃

270 CH₃ CH₃

271 H CH₂CH₃

272 Cl CH₂CH₃

273 CH₃ CH₂CH₃

274 H (CH₂)₂CH₃

275 Cl (CH₂)₂CH₃

276 CH₃ (CH₂)₂CH₃

277 H H

278 Cl H

279 CH₃ H

280 H CH₃

281 Cl CH₃

282 CH₃ CH₃

283 H CH₂CH₃

284 Cl CH₂CH₃

285 CH₃ CH₂CH₃

286 H (CH₂)₂CH₃

287 Cl (CH₂)₂CH₃

288 CH₃ (CH₂)₂CH₃

289 H H

290 Cl H

291 CH₃ H

292 H CH₃

293 Cl CH₃

294 CH₃ CH₃

295 H CH₂CH₃

296 Cl CH₂CH₃

297 CH₃ CH₂CH₃

298 H (CH₂)₂CH₃

299 Cl (CH₂)₂CH₃

300 CH₃ (CH₂)₂CH₃

301 H H

302 Cl H

303 CH₃ H

304 H CH₃

305 Cl CH₃

306 CH₃ CH₃

307 H CH₂CH₃

308 Cl CH₂CH₃

309 CH₃ CH₂CH₃

310 H (CH₂)₂CH₃

311 Cl (CH₂)₂CH₃

312 CH₃ (CH₂)₂CH₃

313 H H

314 Cl H

315 CH₃ H

316 H CH₃

317 Cl CH₃

318 CH₃ CH₃

319 H CH₂CH₃

320 Cl CH₂CH₃

321 CH₃ CH₂CH₃

322 H (CH₂)₂CH₃

323 Cl (CH₂)₂CH₃

324 CH₃ (CH₂)₂CH₃

325 H H

326 Cl H

327 CH₃ H

328 H CH₃

329 Cl CH₃

330 CH₃ CH₃

331 H CH₂CH₃

332 Cl CH₂CH₃

333 CH₃ CH₂CH₃

334 H (CH₂)₂CH₃

335 Cl (CH₂)₂CH₃

336 CH₃ (CH₂)₂CH₃

337 H H

338 Cl H

339 CH₃ H

340 H CH₃

341 Cl CH₃

342 CH₃ CH₃

343 H CH₂CH₃

344 Cl CH₂CH₃

345 CH₃ CH₂CH₃

346 H (CH₂)₂CH₃

347 Cl (CH₂)₂CH₃

348 CH₃ (CH₂)₂CH₃

349 H H

350 Cl H

351 CH₃ H

352 H CH₃

353 Cl CH₃

354 CH₃ CH₃

355 H CH₂CH₃

356 Cl CH₂CH₃

357 CH₃ CH₂CH₃

358 H (CH₂)₂CH₃

359 Cl (CH₂)₂CH₃

360 CH₃ (CH₂)₂CH₃

361 H H

362 Cl H

363 CH₃ H

364 H CH₃

365 Cl CH₃

366 CH₃ CH₃

367 H CH₂CH₃

368 Cl CH₂CH₃

369 CH₃ CH₂CH₃

370 H (CH₂)₂CH₃

371 Cl (CH₂)₂CH₃

372 CH₃ (CH₂)₂CH₃

373 H H CO₂Me 374 H Et CO₂Me 375 H H CO₂Et 376 H Et CO₂Et 377 H HCH₂CO₂Me 378 H Et CH₂CO₂Me 379 H H CH₂CO₂Et 380 H Et CH₂CO₂Et 381 H H(CH₂)₂CO₂Me 382 H Et (CH₂)₂CO₂Me 383 H H (CH₂)₃CO₂Me 384 H Et(CH₂)₃CO₂Me 385 H H (CH₂)₃CO₂Et 386 H Et (CH₂)₃CO₂Et 387 H H (CH₂)₃CO₂Ph388 H Et (CH₂)₃CO₂Ph

Additional preferred compounds according to the invention and theirenantiomers and pharmaceutically acceptable salts thereof arerepresented by Formula (IIIc),

wherein the preferred substituent combinations R^(C), R^(D), and Z areas defined in Table 4c, and Y⁻ is a pharmaceutically acceptable anion asdefined above, and q is 0, 1, 2, or 3. In certain preferred embodiments,the compound is selected from Table 4c wherein q is 0. In otherpreferred aspects, the compound is selected from Table 4c wherein qis 1. In other preferred aspects, the compound is selected from Table 4cwherein q is 2. In yet further preferred aspects, the compound isselected from Table 4c wherein q is 3. The compounds can be madeaccording to the methods generally described below.

TABLE 4c Preferred Combinations of R^(c), R^(D), and Z Substituentsaccording to Formula (IIIc). Combination Number R^(C) R^(D) Z 1 H H

2 C1 H

3 CH₃ H

4 H CH₃

5 C1 CH₃

6 CH₃ CH₃

7 H CH₂CH₃

8 C1 CH₂CH₃

9 CH₃ CH₂CH₃

10 H (CH₂)₂ CH₃

11 Cl (CH₂)₂ CH₃

12 CH₃ (CH₂)₂ CH₃

13 H H

14 Cl H

15 CH₃ H

16 H CH₃

17 C1 CH₃

18 CH₃ CH₃

19 H CH₂CH₃

20 Cl CH₂CH₃

21 CH₃ CH₂CH₃

22 H (CH₂)₂ CH₃

23 Cl (CH₂)₂ CH₃

24 CH₃ (CH₂)₂ CH₃

25 H H

26 Cl H

27 CH₃ H

28 H CH₃

29 Cl CH₃

30 CH₃ CH₃

31 H CH₂CH₃

32 Cl CH₂CH₃

33 CH₃ CH₂CH₃

34 H (CH₂)₂ CH₃

35 Cl (CH₂)₂ CH₃

36 CH₃ (CH₂)₂ CH₃

37 H H

38 C1 H

39 CH₃ H

40 H CH₃

41 C1 CH₃

42 CH₃ CH₃

43 H CH₂CH₃

44 Cl CH₂CH₃

45 CH₃ CH₂CH₃

46 H (CH₂)₂ CH₃

47 Cl (CH₂)₂ CH₃

48 CH₃ (CH₂)₂ CH₃

49 H H

50 C1 H

51 CH₃ H

52 H CH₃

53 C1 CH₃

54 CH₃ CH₃

55 H CH₂CH₃

56 Cl CH₂CH₃

57 CH₃ CH₂CH₃

58 H (CH₂)₂ CH₃

59 Cl (CH₂)₂CH₃

60 CH₃ (CH₂)₂ CH₃

61 H H

62 Cl H

63 CH₃ H

64 H CH₃

65 Cl CH₃

66 CH₃ CH₃

67 H CH₂CH₃

68 Cl CH₂CH₃

69 CH₃ CH₂CH₃

70 H (CH₂)₂ CH₃

71 Cl (CH₂)₂ CH₃

72 CH₃ (CH₂)₂ CH₃

73 H H

74 Cl H

75 CH₃ H

76 H CH₃

77 Cl CH₃

78 CH₃ CH₃

79 H CH₂CH₃

80 Cl CH₂CH₃

81 CH₃ CH₂CH₃

82 H (CH₂)₂ CH₃

83 Cl (CH₂)₂ CH₃

84 CH₃ (CH₂)₂ CH₃

85 H H

86 Cl H

87 CH₃ H

88 H CH₃

89 Cl CH₃

90 CH₃ CH₃

91 H CH₂CH₃

92 Cl CH₂CH₃

93 CH₃ CH₂CH₃

94 H (CH₂)₂ CH₃

95 Cl (CH₂)₂ CH₃

96 CH₃ (CH₂)₂ CH₃

97 H H

98 Cl H

99 CH₃ H

100 H CH₃

101 Cl CH₃

102 CH₃ CH₃

103 H CH₂CH₃

104 Cl CH₂CH₃

105 CH₃ CH₂CH₃

106 H (CH₂)₂ CH₃

107 Cl (CH₂)₂ CH₃

108 CH₃ (CH₂)₂ CH₃

109 H H

110 Cl H

111 CH₃ H

112 H CH₃

113 Cl CH₃

114 CH₃ CH₃

115 H CH₂CH₃

116 Cl CH₂CH₃

117 CH₃ CH₂CH₃

118 H (CH₂)₂ CH₃

119 Cl (CH₂)₂ CH₃

120 CH₃ (CH₂)₂ CH₃

121 H H

122 Cl H

123 CH₃ H

124 H CH₃

125 Cl CH₃

126 CH₃ CH₃

127 H CH₂CH₃

128 Cl CH₂CH₃

129 CH₃ CH₂CH₃

130 H (CH₂)₂ CH₃

131 Cl (CH₂)₂ CH₃

132 CH₃ (CH₂)₂ CH₃

133 H H

134 Cl H

135 CH₃ H

136 H CH₃

137 Cl CH₃

138 CH₃ CH₃

139 H CH₂CH₃

140 Cl CH₂CH₃

141 CH₃ CH₂CH₃

142 H (CH₂)₂ CH₃

143 Cl (CH₂)₂ CH₃

144 CH₃ (CH₂)₂ CH₃

145 H H

146 Cl H

147 CH₃ H

148 H CH₃

149 Cl CH₃

150 CH₃ CH₃

151 H CH₂CH₃

152 Cl CH₂CH₃

153 CH₃ CH₂CH₃

154 H (CH₂)₂ CH₃

155 Cl (CH₂)₂ CH₃

156 CH₃ (CH₂)₂ CH₃

157 H H

158 Cl H

159 CH₃ H

160 H CH₃

161 Cl CH₃

162 CH₃ CH₃

163 H CH₂CH₃

164 Cl CH₂CH₃

165 CH₃ CH₂CH₃

166 H (CH₂)₂ CH₃

167 Cl (CH₂)₂ CH₃

168 CH₃ (CH₂)₂ CH₃

169 H H

170 Cl H

171 CH₃ H

172 H CH₃

173 Cl CH₃

174 CH₃ CH₃

175 H CH₂CH₃

176 Cl CH₂CH₃

177 CH₃ CH₂CH₃

178 H (CH₂)₂ CH₃

179 Cl (CH₂)₂ CH₃

180 CH₃ (CH₂)₂ CH₃

181 H H

182 Cl H

183 CH₃ H

184 H CH₃

185 Cl CH₃

186 CH₃ CH₃

187 H CH₂CH₃

188 Cl CH₂CH₃

189 CH₃ CH₂CH₃

190 H (CH₂)₂ CH₃

191 Cl (CH₂)₂ CH₃

192 CH₃ (CH₂)₂ CH₃

193 H H

194 Cl H

195 CH₃ H

196 H CH₃

197 Cl CH₃

198 CH₃ CH₃

199 H CH₂CH₃

200 Cl CH₂CH₃

201 CH₃ CH₂CH₃

202 H (CH₂)₂ CH₃

203 Cl (CH₂)₂ CH₃

204 CH₃ (CH₂)₂ CH₃

205 H H

206 Cl H

207 CH₃ H

208 H CH₃

209 Cl CH₃

210 CH₃ CH₃

211 H CH₂CH₃

212 Cl CH₂CH₃

213 CH₃ CH₂CH₃

214 H (CH₂)₂ CH₃

215 Cl (CH₂)₂ CH₃

216 CH₃ (CH₂)₂ CH₃

217 H H

218 Cl H

219 CH₃ H

220 H CH₃

221 Cl CH₃

222 CH₃ CH₃

223 H CH₂CH₃

224 Cl CH₂CH₃

225 CH₃ CH₂CH₃

226 H (CH₂)₂ CH₃

227 Cl (CH₂)₂ CH₃

228 CH₃ (CH₂)₂ CH₃

229 H H

230 Cl H

231 CH₃ H

232 H CH₃

233 Cl CH₃

234 CH₃ CH₃

235 H CH₂CH₃

236 Cl CH₂CH₃

237 CH₃ CH₂CH₃

238 H (CH₂)₂ CH₃

239 Cl (CH₂)₂ CH₃

240 CH₃ (CH₂)₂ CH₃

241 H H

242 Cl H

243 CH₃ H

244 H CH₃

245 Cl CH₃

246 CH₃ CH₃

247 H CH₂CH₃

248 Cl CH₂CH₃

249 CH₃ CH₂CH₃

250 H (CH₂)₂ CH₃

251 Cl (CH₂)₂ CH₃

252 CH₃ (CH₂)₂ CH₃

253 H H

254 Cl H

255 CH₃ H

256 H CH₃

257 Cl CH₃

258 CH₃ CH₃

259 H CH₂CH₃

260 Cl CH₂CH₃

261 CH₃ CH₂CH₃

262 H (CH₂)₂ CH₃

263 Cl (CH₂)₂ CH₃

264 CH₃ (CH₂)₂ CH₃

265 H H

266 Cl H

267 CH₃ H

268 H CH₃

269 Cl CH₃

270 CH₃ CH₃

271 H CH₂CH₃

272 Cl CH₂CH₃

273 CH₃ CH₂CH₃

274 H (CH₂)₂ CH₃

275 Cl (CH₂)₂ CH₃

276 CH₃ (CH₂)₂ CH₃

277 H H

278 Cl H

279 CH₃ H

280 H CH₃

281 Cl CH₃

282 CH₃ CH₃

283 H CH₂CH₃

284 Cl CH₂CH₃

285 CH₃ CH₂CH₃

286 H (CH₂)₂ CH₃

287 Cl (CH₂)₂ CH₃

288 CH₃ (CH₂)₂ CH₃

289 H H

290 Cl H

291 CH₃ H

292 H CH₃

293 Cl CH₃

294 CH₃ CH₃

295 H CH₂CH₃

296 Cl CH₂CH₃

297 CH₃ CH₂CH₃

298 H (CH₂)₂ CH₃

299 Cl (CH₂)₂ CH₃

300 CH₃ (CH₂)₂ CH₃

301 H H

302 Cl H

303 CH₃ H

304 H CH₃

305 Cl CH₃

306 CH₃ CH₃

307 H CH₂CH₃

308 Cl CH₂CH₃

309 CH₃ CH₂CH₃

310 H (CH₂)₂ CH₃

311 Cl (CH₂)₂ CH₃

312 CH₃ (CH₂)₂ CH₃

313 H H

314 Cl H

315 CH₃ H

316 H CH₃

317 Cl CH₃

318 CH₃ CH₃

319 H CH₂CH₃

320 Cl CH₂CH₃

321 CH₃ CH₂CH₃

322 H (CH₂)₂ CH₃

323 Cl (CH₂)₂ CH₃

324 CH₃ (CH₂)₂ CH₃

325 H H

326 Cl H

327 CH₃ H

328 H CH₃

329 Cl CH₃

330 CH₃ CH₃

331 H CH₂CH₃

332 Cl CH₂CH₃

333 CH₃ CH₂CH₃

334 H (CH₂)₂ CH₃

335 Cl (CH₂)₂ CH₃

336 CH₃ (CH₂)₂ CH₃

337 H H

338 Cl H

339 CH₃ H

340 H CH₃

341 Cl CH₃

342 CH₃ CH₃

343 H CH₂CH₃

344 Cl CH₂CH₃

345 CH₃ CH₂CH₃

346 H (CH₂)₂ CH₃

347 Cl (CH₂)₂ CH₃

348 CH₃ (CH₂)₂ CH₃

349 H H

350 Cl H

351 CH₃ H

352 H CH₃

353 Cl CH₃

354 CH₃ CH₃

355 H CH₂CH₃

356 Cl CH₂CH₃

357 CH₃ CH₂CH₃

358 H (CH₂)₂ CH₃

359 Cl (CH₂)₂ CH₃

360 CH₃ (CH₂)₂ CH₃

361 H H

362 Cl H

363 CH₃ H

364 H CH₃

365 Cl CH₃

366 CH₃ CH₃

367 H CH₂CH₃

368 Cl CH₂CH₃

369 CH₃ CH₂CH₃

370 H (CH₂)₂CH₃

371 Cl (CH₂)₂CH₃

372 H H CO₂Me 373 H Et CO₂Me 374 H H CO₂Et 375 H Et CO₂Et 376 H HCH₂CO₂Me 377 H Et CH₂CO₂Me 378 H H CH₂CO₂Et 379 H Et CH₂CO₂Et 380 H H(CH₂)₂CO₂Me 381 H Et (CH₂)₂CO₂Me 382 H H (CH₂)₃CO₂Me 383 H Et(CH₂)₃CO₂Me 384 H H (CH₂)₃CO₂Et 385 H Et (CH₂)₃CO₂Et 386 H H (CH₂)₃CO₂Ph387 H Et (CH₂)₃CO₂Ph

Each preferred embodiment described herein can be taken in combinationwith one, any or all other preferred embodiments, as though presentedherein in every permutation.

Compositions of the invention can comprise racemic mixtures, pureenantiomers, or an excess of one enantiomer over the other. For example,a composition can comprise an enantiomeric excess of at least 5, 10, 20,30, 40, 50, 60, 70, 80 or 90%. In one embodiment, the enantiomericexcess is at least 95%.

The compounds of the invention include all enantiomers which may bedefined, in terms of absolute stereochemistry, as (R)— or (S)—, as wellas their racemic and optically pure forms, and is not limited to thosedescribed herein in any of their pharmaceutically acceptable forms,including enantiomers, salts, solvates, polymorphs, solvatomorphs,hydrates, anhydrous and other crystalline forms and combinationsthereof. Likewise, all tautomeric forms are intended to be included.

Preferably, a pharmaceutical composition comprises a compound of theinvention as an R enantiomer in substantially pure form; or, apharmaceutical composition comprises a compound of the invention as an Senantiomer in substantially pure form; or, a pharmaceutical compositioncomprises a compound of the invention as enantiomeric mixtures whichcontain an excess of the R enantiomer or an excess of the S enantiomer.It is particularly preferred that the pharmaceutical compositioncontains a compound of the invention which is a substantially pureoptical isomer. For the avoidance of doubt, a compound of the inventioncan, if desired, be used in the form of solvates.

Synthesis

Compounds having Formula (1) can be prepared using methods analogous tothe following general synthetic schemes:

and,

For example,

and

Additional Biologically Active Agents and Exogenous Large Pore ChannelAgonists

As described above, the compound or composition of the invention can beadministered with a biologically active agent. For example, one or moreadditional biologically active agents, including those typically used totreat neurogenic inflammation, may be used in combination with acompound or composition of the invention described herein. Thebiologically active agents include, but are not limited to, TRP1Areceptor agonists, TRPV1-4 receptor agonists, TRPM8 agonists, ASICagonists, P2X receptor agonists, acetaminophen, NSAIDs, glucocorticoids,narcotics, tricyclic antidepressants, amine transporter inhibitors,anticonvulsants, anti-proliferative and immune modulatory agents, anantibody or antibody fragment, an antibiotic, a polynucleotide, apolypeptide, a protein, an anti-cancer agent, a growth factor, and avaccine.

TRPV1 agonists that can be employed in the methods, kits andcompositions of the invention include, but are not limited to, any thatactivates TRPV1 receptors on nociceptors and allows for entry of atleast one inhibitor of voltage-gated ion channels (for example, acompound of the invention). A suitable TRPV1 agonist is capsaicin oranother capsaicinoids, which are members of the vanilloid family ofmolecules. Naturally occurring capsaicinoids are capsaicin itself,dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin,homocapsaicin, and nonivamide. Other suitable capsaicinoids andcapsaicinoid analogs and derivatives for use in the compositions andmethods of the present invention include naturally occurring andsynthetic capsaicin derivatives and analogs including, e.g., vanilloids(e.g., N-vanillyl-alkanedienamides, N-vanillyl-alkanedienyls, andN-vanillyl-cis-monounsaturated alkenamides), capsiate, dihydrocapsiate,nordihydrocapsiate and other capsinoids, capsiconiate,dihydrocapsiconiate and other coniferyl esters, capsiconinoid,resiniferatoxin, tinyatoxin, civamide, N-phenylmethylalkenamidecapsaicin derivatives, olvanil,N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octa-decanamide,N-oleyl-homovanillamide, triprenyl phenols (e.g., scutigeral),gingerols, piperines, shogaols, guaiacol, eugenol, zingerone, nuvanil,NE-19550, NE-21610, and NE-28345. Additional capsaicinoids, theirstructures, and methods of their manufacture are described in U.S. Pat.Nos. 7,446,226 and 7,429,673, which are hereby incorporated byreference.

Additional suitable TRPV1 agonists include but are not limited toeugenol, arvanil (N-arachidonoylvanillamine), anandamide,2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil (NE19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA),6’-iodoresiniferatoxin (6’-IRTX), C18 N-acylethanolamines, lipoxygenasederivatives such as 12-hydroperoxyeicosatetraenoic acid, inhibitorcysteine knot (ICK) peptides (vanillotoxins), piperine, MSK195(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide),JYL79(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N’-(4-hydroxy-3-methoxybenzyl)thiourea),hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 10-shogaol,oleylgingerol, oleylshogaol, and SU200(N-(4-tert-butylbenzyl)-N′-(4-hydroxy-3-methoxybenzyl)thiourea). Stillother TRPV1 agonists include amylocaine, articaine, benzocaine,bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine,dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine,hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine(oracaine), metabutoxycaine, piperocaine, prilocaine, procaine(novacaine), proparacaine, propoxycaine, risocaine, ropivacaine,tetracaine (amethocaine), and trimecaine.

Suitable TRPV2-4 agonists include, but are not limited to, are 2-APB,cannabinol, diphenylboronic anhydride, insulin-like growth factor 1,lysophosphatidylcholine, lysophosphatidylinositol, probenecid,Δ9-tetrahydrocannabinol, vanillin, eugenol, cinnamaldehyde, camphor,carvacrol, thymol, citral, farnesyl diphosphate, tetrahydrocannabivarin,incensole acetate, diphenylboronic anhydride, 6-tert-butyl-m-cresol,dihydrocarveocarveol, borneol, (-)-menthol, GSK1016790A, 4α-PDH,5,6-epoxyeicosatrienoic acid, 4α-PDD, bisandrographolide, citric acid,phorbol 12-myristate 13-acetate and RN1747.

Suitable TRPM8 agonists include, but are not limited to, are menthol,icilin, eucalyptus, linalool, geraniol, hydroxy-citronellal, WS-3,WS-23, Frescolat MGA, Frescolat ML, PMD 38, CPS125, Coolact P, M8-Ag,AITC, cryosim-3 and Cooling Agent 10.

Suitable ASIC agonists include, but are not limited to,chlorophenylguanidine hydrochloride, GMQ hydrochloride,tetrahydropapaveroline (THP), reticulin, polyamine agmatine,lysophosphatidylcholine, arachidonic acid and neuropeptide SF.

Other biologically active agents which can be employed in the methods,compositions, and kits of the invention include any that activates TRP1Areceptors on nociceptors or pruriceptors and allows for entry of atleast one inhibitor of voltage-gated ion channels. Suitable TRP1Aagonists include but are not limited to cinnamaldehyde,allyl-isothiocynanate (mustard oil), diallyl disulfide, icilin, cinnamonoil, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool,2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methylp-hydroxybenzoate, and 3’-carbamoylbiphenyl-3-yl cyclohexylcarbamate(URB597).

P2X agonists that can be employed in the methods, compositions, and kitsof the invention include any that activates P2X receptors on nociceptorsor pruriceptors and allows for entry of at least one inhibitor ofvoltage-gated ion channels. Suitable P2X agonists include but are notlimited to ATP, α,β-methylene ATP, 2-methylthio-ATP, 2’ and3’-O-(4-benzoylbenzoyl)-ATP, and ATP5’-O-(3-thiotriphosphate).

Other biologically active agents that can be used in combination withthe compounds of the invention include NSAIDs, glucocorticoids,narcotics, tricyclic antidepressants, amine transporter inhibitors,anticonvulsants, anti-proliferative and immune modulatory agents, anantibody or antibody fragment, an antibiotic, a polynucleotide, apolypeptide, a protein, an anti-cancer agent, a growth factor, and avaccine.

Non-steroidal anti-inflammatory drugs (NSAIDs) that can be administeredto a patient (e.g., a human) suffering from neurogenic inflammation incombination with a composition of the invention include, but are notlimited to, acetylsalicylic acid, amoxiprin, benorylate, benorilate,choline magnesium salicylate, diflunisal, ethenzamide, faislamine,methyl salicylate, magnesium salicylate, salicyl salicylate,salicylamide, diclofenac, aceclofenac, acemethacin, alclofenac,bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin,sulindac, tolmetin, ibuprofen, alminoprofen, benoxaprofen, carprofen,dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen,flurbiprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen,naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamicacid, flufenamic acid, meclofenamic acid, tolfenamic acid,phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole,mofebutazone, oxyphenbutazone, phenazone, sulfinpyrazone, piroxicam,droxicam, lornoxicam, meloxicam, tenoxicam, and the COX-2 inhibitorscelecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib,and pharmaceutically acceptable salts thereof.

Glucocorticoids that can be administered to a patient (e.g., a human)suffering from neurogenic inflammation in combination with a compositionof the invention include, but are not limited to, hydrocortisone,cortisone acetate, prednisone, prednisolone, methylprednisolone,dexamethasone, betamethasone, triamcinolone, beclometasone,fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, andpharmaceutically acceptable salts thereof.

Narcotics that can be administered to a patient (e.g., a human)suffering from neurogenic inflammation in combination with a compositionof the invention include, but are not limited, to tramadol, hydrocodone,oxycodone, morphine, and pharmaceutically acceptable salts thereof.

Antiproliferative and immune modulatory agents that can be administeredto a patient (e.g., a human) suffering from neurogenic inflammation incombination with a composition of the invention include, but are notlimited to, alkylating agents, platinum agents, antimetabolites,topoisomerase inhibitors, dihydrofolate reductase inhibitors, antitumorantibiotics, antimitotic agents, aromatase inhibitors, thymidylatesynthase inhibitors, DNA antagonists, farnesyltransferase inhibitors,pump inhibitors, histone acetyltransferase inhibitors, metalloproteinaseinhibitors, ribonucleoside reductase inhibitors, TNF-alpha agonists,TNF-alpha antagonists or scavengers, interleukin 1 (IL-1) antagonists orscavengers, endothelin A receptor antagonists, retinoic acid receptoragonists, hormonal agents, antihormonal agents, photodynamic agents, andtyrosine kinase inhibitors.

The biologically active agents can be administered prior to, concurrentwith, or following administration of a composition of the invention,using any formulation, dosing, or administration known in the art thatis therapeutically effective.

Formulation of Compositions

The administration of the compounds of the invention may be by anysuitable means that results in the reduction of perceived pain sensationat the target region. The compounds of the invention may be contained inany appropriate amount in any suitable carrier substance, and aregenerally present in amounts totaling 1-99% by weight of the totalweight of the composition. The composition may be provided in a dosageform that is suitable for oral, parenteral (e.g., intravenous,intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal,sublingual, nasal, vaginal, intrathecal, epidural, or ocularadministration, or by injection, inhalation, or direct contact with thenasal or oral mucosa.

Thus, the composition may be in the form of, e.g., tablets, capsules,pills, powders, granulates, suspensions, emulsions, solutions, gelsincluding hydrogels, pastes, ointments, creams, plasters, drenches,osmotic delivery devices, suppositories, enemas, injectables, implants,sprays, or aerosols. The compositions may be formulated according toconventional pharmaceutical practice (see, e.g., Remington: The Scienceand Practice of Pharmacy, 22nd edition, 2013, ed. L.V. Allen,Pharmaceutical Press, Philadelphia, and Encyclopedia of PharmaceuticalTechnology, 4^(th) Edition, ed. J. Swarbrick, 2013, CRC Press, NewYork).

Each compound may be formulated in a variety of ways that are known inthe art. For example, a compound of the invention and a biologicallyactive agent as defined herein may be formulated together or separately.Desirably, a compound of the invention and a biologically active agentare formulated together for their simultaneous or near simultaneousadministration. In another embodiment, two or more biologically activeagents may be formulated together with a compound of the invention, orseparately. Other examples include, but are not limited to, two or morecompounds of the invention formulated together, wherein the compoundsare formulated together with or without one or more biologically activeagents.

The individually or separately formulated agents can be packagedtogether as a kit. Non-limiting examples include but are not limited tokits that contain, e.g., two pills, a pill and a powder, a suppositoryand a liquid in a vial, two topical creams, etc. The kit can includeoptional components that aid in the administration of the unit dose topatients, such as vials for reconstituting powder forms, syringes forinjection, customized IV delivery systems, inhalers, etc. Additionally,the unit dose kit can contain instructions for preparation andadministration of the compositions.

The kit may be manufactured as a single use unit dose for one patient,multiple uses for a particular patient (at a constant dose or in whichthe individual compounds may vary in potency as therapy progresses); orthe kit may contain multiple doses suitable for administration tomultiple patients (“bulk packaging”). The kit components may beassembled in cartons, blister packs, bottles, tubes, and the like.

Controlled Release Formulations

Each compound of the invention, alone or in combination with one or moreof the biologically active agents as described herein, can be formulatedfor controlled release (e.g., sustained or measured) administration, asdescribed in U.S. Pat. Application Publication Nos. 2003/0152637 and2005/0025765, each incorporated herein by reference. For example, acompound of the invention, alone or in combination with one or more ofthe biologically active agents as described herein, can be incorporatedinto a capsule or tablet that is administered to the patient.

Any pharmaceutically acceptable vehicle or formulation suitable forlocal application and/or injection into a site to be treated (e.g., apainful surgical incision, wound, or joint), that is able to provide asustained release of compound of the invention, alone or in combinationwith one or more of the biologically active agents as described herein,may be employed to provide for prolonged elimination or alleviation ofinflammation, as needed. Controlled release formulations known in theart include specially coated pellets, polymer formulations or matricesfor surgical insertion or as sustained release microparticles, e.g.,microspheres or microcapsules, for implantation, insertion, infusion orinjection, wherein the slow release of the active medicament is broughtabout through sustained or controlled diffusion out of the matrix and/orselective breakdown of the coating of the preparation or selectivebreakdown of a polymer matrix. Other formulations or vehicles forcontrolled, sustained or immediate delivery of an agent to a preferredlocalized site in a patient include, e.g., suspensions, emulsions, gels,liposomes and any other suitable art known delivery vehicle orformulation acceptable for subcutaneous or intramuscular administration.

A wide variety of biocompatible materials may be utilized as acontrolled release carrier to provide the controlled release of acompound of the invention, alone or in combination with one or morebiologically active agents, as described herein. Any pharmaceuticallyacceptable biocompatible polymer known to those skilled in the art maybe utilized. It is preferred that the biocompatible controlled releasematerial degrade in vivo within about one year, preferably within about3 months, more preferably within about two months. More preferably, thecontrolled release material will degrade significantly within one tothree months, with at least 50% of the material degrading into non-toxicresidues, which are removed by the body, and 100% of the compound of theinvention being released within a time period within about two weeks,preferably within about 2 days to about 7 days. A degradable controlledrelease material should preferably degrade by hydrolysis, either bysurface erosion or bulk erosion, so that release is not only sustainedbut also provides desirable release rates. However, the pharmacokineticrelease profile of these formulations may be first order, zero order,bi- or multi-phasic, to provide the desired reversible localanti-nociceptive effect over the desired time period.

Suitable biocompatible polymers can be utilized as the controlledrelease material. The polymeric material may comprise biocompatible,biodegradable polymers, and in certain preferred embodiments, ispreferably a copolymer of lactic and glycolic acid. Preferred controlledrelease materials which are useful in the formulations of the inventioninclude the polyanhydrides, polyesters, co-polymers of lactic acid andglycolic acid (preferably wherein the weight ratio of lactic acid toglycolic acid is no more than 4:1 i.e., 80% or less lactic acid to 20%or more glycolic acid by weight) and polyorthoesters containing acatalyst or degradation enhancing compound, for example, containing atleast 1% by weight anhydride catalyst such as maleic anhydride. Examplesof polyesters include polylactic acid, polyglycolic acid and polylacticacid-polyglycolic acid copolymers. Other useful polymers include proteinpolymers such as collagen, gelatin, fibrin and fibrinogen andpolysaccharides such as hyaluronic acid.

The polymeric material may be prepared by any method known to thoseskilled in the art. For example, where the polymeric material iscomprised of a copolymer of lactic and glycolic acid, this copolymer maybe prepared by the procedure set forth in U.S. Pat. No. 4,293,539,incorporated herein by reference. Alternatively, copolymers of lacticand glycolic acid may be prepared by any other procedure known to thoseskilled in the art. Other useful polymers include polylactides,polyglycolides, polyanhydrides, polyorthoesters, polycaprolactones,polyphosphazenes, polyphosphoesters, polysaccharides, proteinaceouspolymers, soluble derivatives of polysaccharides, soluble derivatives ofproteinaceous polymers, polypeptides, polyesters, and polyorthoesters ormixtures or blends of any of these.

Pharmaceutically acceptable polyanhydrides which are useful in thepresent invention have a water-labile anhydride linkage. The rate ofdrug release can be controlled by the particular polyanhydride polymerutilized and its molecular weight. The polysaccharides may bepoly-1,4-glucans, e.g., starch glycogen, amylose, amylopectin, andmixtures thereof. The biodegradable hydrophilic or hydrophobic polymermay be a water-soluble derivative of a poly-1,4-glucan, includinghydrolyzed amylopectin, derivatives of hydrolyzed amylopectin such ashydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch, andthe like. The polyanhydride polymer may be branched or linear.

Examples of polymers which are useful in the present invention include(in addition to homopolymers and copolymers of poly(lactic acid) and/orpoly(glycolic acid)) poly[bis(p-carboxyphenoxy) propane anhydride](PCPP), poly[bis(p-carboxy)methane anhydride] (PCPM), polyanhydrides ofoligomerized unsaturated aliphatic acids, polyanhydride polymersprepared from amino acids which are modified to include an additionalcarboxylic acid, aromatic polyanhydride compositions, and co-polymers ofpolyanhydrides with other substances, such as fatty acid terminatedpolyanhydrides, e.g., polyanhydrides polymerized from monomers of dimersand/or trimers of unsaturated fatty acids or unsaturated aliphaticacids. Polyanhydrides may be prepared in accordance with the methods setforth in U.S. Pat. No. 4,757,128, incorporated herein by reference.Polyorthoester polymers may be prepared, e.g., as set forth in U.S. Pat.No. 4,070,347, incorporated herein by reference. Polyphosphoesters maybe prepared and used as set forth in U.S. Pat. Nos. 6,008,318,6,153,212, 5,952,451, 6,051,576, 6,103,255, 5,176,907 and 5,194,581,each of which is incorporated herein by reference.

Proteinaceous polymers may also be used. Proteinaceous polymers andtheir soluble derivatives include gelation biodegradable syntheticpolypeptides, elastin, alkylated collagen, alkylated elastin, and thelike. Biodegradable synthetic polypeptides includepoly-(N-hydroxyalkyl)-L-asparagine, poly-(N-hydroxyalkyl)-L-glutamine,copolymers of N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutaminewith other amino acids. Suggested amino acids include L-alanine,L-lysine, L-phenylalanine, L-valine, L-tyrosine, and the like.

In additional embodiments, the controlled release material, which ineffect acts as a carrier for a compound of the invention, alone or incombination with one or more biologically active agents as describedherein, can further include a bioadhesive polymer such as pectins(polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) ornon-toxic lectins or the polymer itself may be bioadhesive, e.g.,polyanhydride or polysaccharides such as chitosan.

In embodiments where the biodegradable polymer comprises a gel, one suchuseful polymer is a thermally gelling polymer, e.g., polyethylene oxide,polypropylene oxide (PEO-PPO) block copolymer such as Pluronic™ F127from BASF Wyandotte. In such cases, the local anesthetic formulation maybe injected via syringe as a free-flowing liquid, which gels rapidlyabove 30° C. (e.g., when injected into a patient). The gel system thenreleases a steady dose of a compound of the invention, alone or incombination with one or more biologically active agents as describedherein, at the site of administration.

Dosage Forms for Oral Use

Formulations for oral use include tablets containing the activeingredient(s) in a mixture with non-toxic pharmaceutically acceptableexcipients. These excipients may be, for example, inert diluents orfillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystallinecellulose, starches including potato starch, calcium carbonate, sodiumchloride, lactose, calcium phosphate, calcium sulfate, or sodiumphosphate); granulating and disintegrating agents (e.g., cellulosederivatives including microcrystalline cellulose, starches includingpotato starch, croscarmellose sodium, alginates, or alginic acid);binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid,sodium alginate, gelatin, starch, pregelatinized starch,microcrystalline cellulose, magnesium aluminum silicate,carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethyleneglycol); and lubricating agents, glidants, and antiadhesives (e.g.,magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenatedvegetable oils, or talc). Other pharmaceutically acceptable excipientscan be colorants, flavoring agents, plasticizers, humectants, bufferingagents, taste masking agents (such as hydroxypropyl methylcellulose,hydroxypropyl cellulose), and the like.

One or more compounds of the invention and one or more biologicallyactive agents, as defined herein, may be mixed together in a tablet,capsule, or other vehicle, or may be partitioned. In one example, acompound of the invention is contained on the inside of the tablet, andthe biologically active agent is on the outside of the tablet, such thata substantial portion of the biologically active agent is released priorto the release of the compound of the invention.

Formulations for oral use may also be provided as chewable tablets, oras hard gelatin capsules wherein the active ingredient is mixed with aninert solid diluent (e.g., potato starch, lactose, microcrystallinecellulose, calcium carbonate, calcium phosphate or kaolin), or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example, peanut oil, liquid paraffin, or olive oil.Powders, granulates, and pellets may be prepared using the ingredientsmentioned above under tablets and capsules in a conventional mannerusing, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

Formulations for oral administration to the mouth may also be providedas a mouthwash, an oral spray, oral rinse solution, oral ointment, ororal gel.

Dissolution or diffusion controlled release can be achieved byappropriate coating of a tablet, capsule, pellet, or granulateformulation of compounds, or by incorporating the compound into anappropriate matrix. A controlled release coating may include one or moreof the coating substances mentioned above and/or, e.g., shellac,beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glycerylmonostearate, glyceryl distearate, glycerol palmitostearate,ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetatebutyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone,polyethylene, polymethacrylate, methylmethacrylate,2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol,ethylene glycol methacrylate, and/or polyethylene glycols. In acontrolled release matrix formulation, the matrix material may alsoinclude, e.g., hydrated methylcellulose, carnauba wax and stearylalcohol, carbopol 934, silicone, glyceryl tristearate, methylacrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/orhalogenated fluorocarbon.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally include aqueoussolutions, suitably flavored syrups, aqueous or oil suspensions, andflavored emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil, or peanut oil, as well as elixirs and similarpharmaceutical vehicles.

Generally, when administered to a human, the oral dosage of any of thecompounds of the combination of the invention will depend on the natureof the compound, and can readily be determined by one skilled in theart. Typically, such dosage is normally about 0.001 mg to 2000 mg perday, desirably about 1 mg to 1000 mg per day, and more desirably about 5mg to 500 mg per day. Dosages up to 200 mg per day may be necessary.

Administration of each drug in a combination therapy, as describedherein, can, independently, be one to four times daily for one day toone year, and may even be for the life of the patient. Chronic,long-term administration will be indicated in many cases.

Parenteral Formulations

Formulations suitable for parenteral administration (e.g., byinjection), include aqueous or non-aqueous, isotonic, pyrogen-free,sterile liquids (e.g., solutions, suspensions), in which the compound isdissolved, suspended, or otherwise provided (e.g., in a liposome orother microparticulate). Such liquids may additional contain otherpharmaceutically acceptable ingredients, such as anti-oxidants, buffers,preservatives, stabilizers, bacteriostats, suspending agents, thickeningagents, and solutes which render the formulation isotonic with the blood(or other relevant bodily fluid) of the intended recipient. Examples ofexcipients include, for example, water, alcohols, polyols, glycerol,vegetable oils, and the like. Examples of suitable isotonic carriers foruse in such formulations include Sodium Chloride Injection, Ringer’sSolution, or Lactated Ringer’s Injection. Typically, the concentrationof the compound in the liquid is from about 1 ng/ml to about 10 µg/ml,for example from about 10 ng/ml to about 1 µg/ml. The formulations maybe presented in unit-dose or multi-dose sealed containers, for example,ampoules and vials, and may be stored in a freeze-dried (lyophilised)condition requiring only the addition of the sterile liquid carrier, forexample water for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules, and tablets.

Topical Formulations

The compositions of the invention, alone or in combination with one ormore of the biologically active agents described herein, can also beadapted for topical use with a topical vehicle containing from between0.0001% and 25% (w/w) or more of active ingredient(s).

In a preferred combination, the active ingredients are preferably eachfrom between 0.0001% to 10% (w/w), more preferably from between 0.0005%to 4% (w/w) active agent. The topical formulation, including but notlimited to a cream, gel, or ointment, can be applied one to four timesdaily, or as needed. Performing the methods described herein, thetopical vehicle containing the composition of the invention, or acombination therapy containing a composition of the invention ispreferably applied to the site of inflammation on the patient. Forexample, a cream may be applied to the hands of a patient suffering fromarthritic fingers.

The compositions can be formulated using any dermatologically acceptablecarrier. Exemplary carriers include a solid carrier, such as alumina,clay, microcrystalline cellulose, silica, or talc; and/or a liquidcarrier, such as an alcohol, a glycol, or a water-alcohol/glycol blend.The therapeutic agents may also be administered in liposomalformulations that allow therapeutic agents to enter the skin. Suchliposomal formulations are described in U.S. Pat. Nos. 5,169,637;5,000,958; 5,049,388; 4,975,282; 5,194,266; 5,023,087; 5,688,525;5,874,104; 5,409,704; 5,552,155; 5,356,633; 5,032,582; 4,994,213;8,822,537, and PCT Publication No. WO 96/40061. Examples of otherappropriate vehicles are described in U.S. Pat. Nos. 4,877,805,8,822,537, and EP Publication No. 0586106A1. Suitable vehicles of theinvention may also include mineral oil, petrolatum, polydecene, stearicacid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, orvegetable oil.

The composition can further include a skin penetrating enhancer, such asthose described in “Percutaneous Penetration enhancers”, (eds. Smith E Wand Maibach H I. CRC Press 1995). Exemplary skin penetrating enhancersinclude alkyl (N,N-disubstituted amino alkanoate) esters, such asdodecyl 2-(N,N dimethylamino) propionate (DDAIP), which is described inpatents U.S. Pat. Nos. 6,083,996 and 6,118,020, which are bothincorporated herein by reference; a water-dispersible acid polymer, suchas a polyacrylic acid polymer, a carbomer (e.g., Carbopol™ or Carbopol940P™, available from B. F. Goodrich Company (Akron, Ohio)), copolymersof polyacrylic acid (e.g., Pemulen™ from B. F. Goodrich Company orPolycarbophil™ from A. H. Robbins, Richmond, Va.; a polysaccharide gum,such as agar gum, alginate, carrageenan gum, ghatti gum, karaya gum,kadaya gum, rhamsan gum, xanthan gum, and galactomannan gum (e.g., guargum, carob gum, and locust bean gum), as well as other gums known in theart (see for instance, Industrial Gums: Polysaccharides & TheirDerivatives, Whistler R. L., BeMiller J. N. (eds.), 3rd Ed. AcademicPress (1992) and Davidson, R. L., Handbook of Water-Soluble Gums &Resins, McGraw-Hill, Inc., N.Y. (1980)); or combinations thereof.

Other suitable polymeric skin penetrating enhancers are cellulosederivatives, such as ethyl cellulose, methyl cellulose, hydroxypropylcellulose. Additionally, known transdermal penetrating enhancers canalso be added, if desired. Illustrative are dimethyl sulfoxide (DMSO)and dimethyl acetamide (DMA), 2-pyrrolidone, N,N-diethyl-m-toluamide(DEET), 1-dodecylazacycloheptane-2-one (AZONE™, a registered trademarkof Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone,calcium thioglycolate and other enhancers such as dioxolanes, cyclicketones, and their derivatives and so on.

Also illustrative are a group of biodegradable absorption enhancerswhich are alkyl N,N-2-(disubstituted amino) alkanoates as described inU.S. Pat. No. 4,980,378 and U.S. Pat. No. 5,082,866, which are bothincorporated herein by reference, including: tetradecyl(N,N-dimethylamino) acetate, dodecyl (N,N-dimethylamino) acetate, decyl(N,N-dimethylamino) acetate, octyl (N,N-dimethylamino) acetate, anddodecyl (N,N-diethylamino) acetate.

Particularly preferred skin penetrating enhancers include isopropylmyristate; isopropyl palmitate; dimethyl sulfoxide; decyl methylsulfoxide; dimethylalanine amide of a medium chain fatty acid; dodecyl2-(N,N-dimethylamino) propionate or salts thereof, such as its organic(e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acidaddition salts) and inorganic salts (e.g., acetic, benzoic, salicylic,glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic,methanesulfonic, cyclohexanesulfamic, picric, and lactic acid additionsalts), as described in U.S. Pat. No. 6,118,020; and alkyl2-(N,N-disubstituted amino)-alkanoates, as described in U.S. Pat. No.4,980,378 and U.S. Pat. No. 5,082,866.

The skin penetrating enhancer in this composition by weight would be inthe range of 0.5% to 10% (w/w). The most preferred range would bebetween 1.0% and 5% (w/w). In another embodiment, the skin penetratingenhancer comprises between 0.5%-1%, 1%-2%, 2%-3%, 3%-4%, or 4%-5%, (w/w)of the composition.

The compositions can be provided in any useful form. For example, thecompositions of the invention may be formulated as solutions, emulsions(including microemulsions), suspensions, creams, ointments, foams,lotions, gels, powders, or other typical solid, semisolid, or liquidcompositions (e.g., topical sprays) used for application to the skin orother tissues where the compositions may be used. Such compositions maycontain other ingredients typically used in such products, such ascolorants, fragrances, thickeners (e.g., xanthan gum, a fatty acid, afatty acid salt or ester, a fatty alcohol, a modified cellulose, amodified mineral material, Krisgel 100™, or a synthetic polymer),antimicrobials, solvents, surfactants, detergents, gelling agents,antioxidants, fillers, dyestuffs, viscosity-controlling agents,preservatives, humectants, emollients (e.g., natural or synthetic oils,hydrocarbon oils, waxes, or silicones), hydration agents, chelatingagents, demulcents, solubilizing excipients, adjuvants, dispersants,skin penetrating enhancers, plasticizing agents, preservatives,stabilizers, demulsifiers, wetting agents, sunscreens, emulsifiers,moisturizers, astringents, deodorants, and optionally includinganesthetics, anti-itch actives, botanical extracts, conditioning agents,darkening or lightening agents, glitter, humectants, mica, minerals,polyphenols, silicones or derivatives thereof, sunblocks, vitamins, andphytomedicinals.

The compositions can also include other like ingredients to provideadditional benefits and improve the feel and/or appearance of thetopical formulation. Specific classes of additives commonly use in theseformulations include: isopropyl myristate, sorbic acid NF powder,polyethylene glycol, phosphatidylcholine (including mixtures ofphosphatidylcholine, such as phospholipon G), Krisgel 100™ distilledwater, sodium hydroxide, decyl methyl sulfoxide (as a skin penetratingenhancer), menthol crystals, lavender oil, butylated hydroxytoluene,ethyl diglycol reagent, and 95% percent (190 proof) ethanol.

Formulations for Ophthalmic Administration

The compounds of the invention can also be formulated with anophthalmically acceptable carrier in sufficient concentration so as todeliver an effective amount of the active compound or compounds to theoptic nerve site of the eye. Preferably, the ophthalmic, therapeuticsolutions contain one or more of the active compounds in a concentrationrange of approximately 0.0001% to approximately 5% (weight by volume)and more preferably approximately 0.0005% to approximately 0.1% (weightby volume).

An ophthalmically acceptable carrier does not cause significantirritation to the eye and does not abrogate the pharmacological activityand properties of the charged sodium channel blockers.

Ophthalmically acceptable carriers are generally sterile, essentiallyfree of foreign particles, and generally have a pH in the range of 5-8.Preferably, the pH is as close to the pH of tear fluid (7.4) aspossible. Ophthalmically acceptable carriers are, for example, sterileisotonic solutions such as isotonic sodium chloride or boric acidsolutions. Such carriers are typically aqueous solutions contain sodiumchloride or boric acid. Also useful are phosphate buffered saline (PBS)solutions.

Various preservatives may be used in the ophthalmic preparation.Preferred preservatives include, but are not limited to, benzalkoniumpotassium, chlorobutanol, thimerosal, phenylmercuric acetate, andphenylmercuric nitrate. Likewise, various preferred vehicles may be usedin such ophthalmic preparation. These vehicles include, but are notlimited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose,poloxamers, carboxymethyl cellulose and hydroxyethyl cellulose.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, etc., mannitol and glycerin, or any other suitableophthalmically acceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude but are not limited to, acetate buffers, citrate buffers,phosphate buffers, and borate buffers. Acids or bases may be used toadjust the pH of these formulations as needed. Ophthalmically acceptableantioxidants can also be include. Antioxidants include but are notlimited to sodium metabisulfite, sodium thiosulfate, acetylcysteine,butylated hydroxyanisole, and butylated hydroxytoluene.

Formulations for Nasal and Inhalation Administration

The pharmaceutical compositions of the invention can be formulated fornasal or intranasal administration. Formulations suitable for nasaladministration, when the carrier is a solid, include a coarse powderhaving a particle size, for example, in the range of approximately 20 to500 microns which is administered by rapid inhalation through the nasalpassage. When the carrier is a liquid, for example, a nasal spray or asnasal drops, one or more of the formulations can be admixed in anaqueous or oily solution and inhaled or sprayed into the nasal passage.

For administration by inhalation, the active ingredient can beconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebulizer, with the use of a suitable propellant,e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount, Capsules and cartridgesof, for example, gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of, forexample, gelatin or blisters of, for example, laminated aluminum foil,for use in an inhaler or insufflator. Powder blend formulationsgenerally contain a powder mix for inhalation of the compound of theinvention and a suitable powder base (carrier/diluent/excipientsubstance) such as mono-, di or ploy-saccharides (e.g. lactose orstarch). Use of lactose is preferred. In one embodiment, each capsule orcartridge may contain between about 2 ug to about 100 mg of the compoundof formula (I) optionally in combination with another therapeuticallyactive ingredient. In a preferred embodiment, each capsule or cartridgemay contain between about 10 ug to about 50 mg of the compound offormula (I) optionally in combination with another therapeuticallyactive ingredient. In another embodiment, each capsule or cartridge maycontain between about 20 ug to about 10 mg of the compound of formula(I) optionally in combination with another therapeutically activeingredient. Alternatively, the compound of the invention may bedelivered without excipients.

Suitably, the packaging/medicament dispenser is of a type selected fromthe group consisting of a reservoir dry powder inhaler (RDPI), a singleuse inhaler (e.g., capsule or blister inhaler), a multi-dose dry powderinhaler (MDPI), and a metered dose inhaler (MDI).

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain an aqueousmedium, ethanol, aqueous ethanol, or a suitable alternative agent fordispersing, solubilizing, or extending release of the activeingredient(s); a propellant as solvent; and/or a surfactant, such assorbitan trioleate, oleic acid, or an oligolactic acid.

Compositions formulated for nasal or inhalation administration mayinclude one or more taste-masking agents such as flavoring agents,sweeteners, and other strategies, such as sucrose, dextrose, andlactose, carboxylic acids, menthol, amino acids or amino acidderivatives such as arginine, lysine, and monosodium glutamate, and/orsynthetic flavor oils and flavoring aromatics and/or natural oils,extracts from plants, leaves, flowers, fruits, etc., and combinationsthereof. These may include cinnamon oils, oil of wintergreen, peppermintoils, clover oil, bay oil, anise oil, eucalyptus, vanilla, citrus oilsuch as lemon oil, orange oil, grape and grapefruit oil, fruit essencesincluding apple, peach, pear, strawberry, raspberry, cherry, plum,pineapple, apricot, etc. Additional sweeteners include sucrose,dextrose, aspartame, acesulfame-K, sucralose and saccharin, organicacids (by non-limiting example citric acid and aspartic acid). Suchflavors may be present at from about 0.05 to about 4 percent by weight,and may be present at lower or higher amounts as a factor of one or moreof potency of the effect on flavor, solubility of the flavorant, effectsof the flavorant on solubility or other physicochemical orpharmacokinetic properties of other formulation components, or otherfactors.

Indications

The compounds, compositions, methods, and kits of the invention can beused to treat pain, cough or itch associated with any of a number ofconditions, including trigeminal trophic syndrome, erythromelalgia, backand neck pain, lower back pain, cancer pain, gynecological and laborpain, abdominal wall pain, chronic abdominal wall pain, fibromyalgia,allergic rhinitis, arthritis, rheumatoid arthritis, osteoarthritis,rheumatological pains, orthopedic pains, acute and post herpeticneuralgia and other neuropathic pains (including peripheral neuropathy),sickle cell crises, muscle pain, vulvodynia, rectal pain, Levator anisyndrome, proctalgia fugax, peri-anal pain, hemorrhoid pain, stomachpain, ulcers, inflammatory bowel disease, irritable bowel disease,irritable bowel syndrome, oral mucositis, esophagitis, interstitialcystitis, urethritis and other urological pains, dental pain, burn pain,headaches, ophthalmic irritation, conjunctivitis (e.g., allergicconjunctivitis), eye redness, dry eye, dry eye syndrome (chronic ocularpain), complex regional pain syndrome, acute postoperative pain,postoperative pain, post-surgical ocular pain, and procedural pain(i.e., pain associated with injections, draining an abscess, surgery,dental procedures, ophthalmic procedures, ophthalmic irritation,conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye,arthroscopies and use of other medical instrumentation, cosmeticsurgical procedures, dermatological procedures, setting fractures,biopsies, and the like).

Since a subclass of nociceptors mediate itch sensation, the compounds,compositions, methods, and kits of the invention can also be used totreat itch in patients with conditions like pruritus (including, but notlimited to, brachioradial, chronic idiopathic, genital/anal, notalgiaparesthetica, and scalp), allergic dermatitis, atopic dermatitis,contact dermatitis, poison ivy, infections, parasites, insect bites,pregnancy, metabolic disorders, liver or renal failure, drug reactions,allergic reactions, eczema, hand eczema, genital and anal itch,hemorrhoid itch, and cancer.

Since a subclass of nociceptors can initiate aberrant cough reflexes,the compounds, compositions, methods, and kits of the invention can alsobe used to treat cough in patients with conditions like asthma, COPD,asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis(IPF), idiopathic pulmonary fibrosis, post viral cough, post-infectioncough, chronic idiopathic cough and lung cancer.

The compounds, compositions, methods, and kits of the invention can alsobe used to treat neurogenic inflammation and neurogenic inflammatorydisorders. Inflammation is a complex set of responses to harmful stimulithat results in localized redness, swelling, and pain. Inflammation canbe innate or adaptive, the latter driven by antigens and is mediated byimmune cells (immune-mediated inflammation). Neurogenic inflammationresults from the efferent functions of pain-sensing neurons(nociceptors), wherein neuropeptides and other chemicals that arepro-inflammatory mediators are released from the peripheral terminals ofthe nociceptors when they are activated. This release process ismediated by calcium influx and exocytosis of peptide containingvesicles, and the pro-inflammatory neuropeptides include substance P,neurokinin A and B (collectively known as tachykinins), calcitoningene-related peptide (CGRP), and vasoactive intestinal polypeptide(VIP).

The release of peripheral terminal chemicals stimulate a variety ofinflammatory responses. First, the release of substance P can result inan increase in capillary permeability such that plasma proteins leakfrom the intravascular compartment into the extracellular space (plasmaextravasation), causing edema. This can be detected as a wheal (a firm,elevated swelling of the skin) which is one component of a triad ofinflammatory responses—wheal, red spot, and flare-known as the Lewistriple response. Second, the release of CGRP causes vasodilation,leading to increased blood flow. This can be detected as a flare, whichis another component of the Lewis triple response.

Substance P also has a pro-inflammatory action on immune cells (e.g.macrophages, T-cells, mast cells, and dendritic cells) via theirneurokinin-1 (NK1) receptor. This effect has been documented in allergicrhinitis, gastritis, and colitis, and represents an interface betweenthe neurogenic and immune-mediated components of inflammation. SubstanceP released from one nociceptor may also act on NK1 receptors onneighboring nociceptors to sensitize or activate them, causing a spreadof activation and afferent/efferent function. These efferent functionsof nociceptors can be triggered by: 1) Direct activation of a nociceptorterminal by a peripheral adequate stimulus applied to the terminal (e.g.a pinch); 2) Indirect antidromic activation of a non-stimulatednociceptor terminal by the axon reflex, wherein action potential inputfrom one terminal of a nociceptor, upon reaching a converging axonalbranch point in the periphery, results in an action potential travelingfrom the branch point down to the peripheral terminal of anon-stimulated terminal; and 3) Activation as a result of activity innociceptor central terminals in the CNS traveling to the periphery(e.g., primary afferent depolarization of central terminals produced byGABA can be sufficient to initiate action potentials traveling the“wrong way”).

Genomic analysis of lung resident ILC2 cells has revealed expression ofreceptors for several neuropeptides released by sensory neurons,including SP, CGRP and VIP, providing an opportunity for nociceptors todirectly communicate with these cells. In particular, VIP is found to beexpressed in NaV1.8+ nodose ganglion neurons, including lung afferentsin OVA-exposed mice. Cultured nodose ganglion neurons stimulated withcapsaicin or IL5 also released VIP while BALF from OVA-exposed micecontained elevated VIP compared to vehicle-challenged mice (Talbot etal., Neuron. 2015 July 15; 87(2): 341-354). These data indicate that VIPis released in the inflamed lung and can be blocked by silencing neuronswith charged sodium channel blockers of the present invention. Inaddition, when CD4+ T cells cultured under T_(H)2 skewing conditionswere exposed to recombinant mouse VIP, the transcript levels of IL-13and IL-5 increased, suggesting that VIP contributes to the competence ofT_(H)2 cells to transcribe these type II regulatory cytokines.

Immune mediator release from immune cells can also activate nociceptors.Mast cells are found close to primary nociceptive neurons and contributeto nociceptor sensitization in a number of contexts. Injection of thesecretagogue compound 48/80 promotes degranulation of mast cells in thedura and leads to excitation of meningeal nociceptors. Mast celldegranulation also contributes to the rapid onset of nerve growthfactor-induced thermal hyperalgesia. Macrophages contribute tonociceptor sensitization by releasing several soluble mediators.Expression of the chemokine macrophage inflammatory protein-1α (MIP-1α)and its receptors CCR1 and CCR5 is increased in macrophages and Schwanncells after partial ligation of the sciatic nerve and contributes to thedevelopment of neuropathic pain. Lymphocytes contribute to thesensitization of peripheral nociceptors. T cells infiltrate the sciaticnerve and dorsal root ganglion (DRG) after nerve injury. Hyperalgesiaand allodynia induced by nerve injury are markedly attenuated orabrogated in rodents lacking T cells and the immunosuppressant rapamycinattenuates neuropathic pain in rats, partly owing to an effect on Tcells. Among the subsets of T cells, type 1 and 2 helper T cells (T_(H)1and T_(H)2 cells) have been shown to have different roles in neuropathicpain. T_(H)1 cells facilitate neuropathic pain behavior by releasingproinflammatory cytokines (IL-2 and interferon-y (IFNγ)), whereas T_(H)2cells inhibit it by releasing anti-inflammatory cytokines (IL-4, IL-10and IL-13). The complement system also has a role in inflammatoryhyperalgesia and neuropathic pain. C5a, an anaphylatoxin, is animportant effector of the complement cascade and upon binding to C5aR1receptors on neutrophils it becomes a potent neutrophil attractant (Ren& Dubner, Nat. Med. 16:1267-1276 (2010)).

Bacterial infections have been shown to directly activate nociceptors,and that the immune response mediated through TLR2, MyD88, T cells, Bcells, and neutrophils and monocytes is not necessary for Staphylococcusaureus-induced pain in mice (Chiu et al., Nature 501:52-57 (2013)).Mechanical and thermal hyperalgesia in mice is correlated with livebacterial load rather than tissue swelling or immune activation.Bacteria induce calcium flux and action potentials in nociceptorneurons, in part via bacterial N-formylated peptides and thepore-forming toxin α-haemolysin, through distinct mechanisms. Specificablation of Nav1.8-lineage neurons, which include nociceptors, abrogatedpain during bacterial infection, but concurrently increased local immuneinfiltration and lymphadenopathy of the draining lymph node. Thus,bacterial pathogens produce pain by directly activating sensory neuronsthat modulate inflammation, an unsuspected role for the nervous systemin host-pathogen interactions. Data from Talbot et al., (Neuron. 2015July 15; 87(2): 341-354) have also suggested that nociceptors areactivated during exposure to allergens in sensitized animals.

In certain disorders, neurogenic inflammation contributes to theperipheral inflammation elicited by tissue injury, autoimmune disease,infection, and exposure to irritants in soft tissue, skin, therespiratory system, joints, the urogenital and GI tract, the liver, andthe brain. Neurogenic inflammatory disorders include, but are notlimited to, allergic inflammation, inflammatory bowel disease,interstitial cystitis, atopic dermatitis, asthma, conjunctivitis,arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis,gastritis, migraine headache, psoriasis, rhinitis, rosacea, sunburn,pancreatitis, chronic cough, chronic rhinosinusistis, traumatic braininjury, polymicrobial sepsis, tendinopathies, chronic urticaria,rheumatic disease, acute lung injury, exposure to irritants, inhalationof irritants, pollutants, or chemical warfare agents, as describedherein.

Assessment of Pain, Cough, Itch, and Neurogenic Inflammation

In order to measure the efficacy of any of the compounds, compositions,methods, and kits of the invention in the treatment of pain associatedwith musculoskeletal, immunoinflammatory and neuropathic disorders, ameasurement index may be used. Indices that are useful include a visualanalog scale (VAS), a Likert scale, categorical pain scales,descriptors, the Lequesne index, the WOMAC index, and the AUSCAN index,each of which is well known in the art. Such indices may be used tomeasure pain, itch, function, stiffness, or other variables.

A visual analog scale (VAS) provides a measure of a one-dimensionalquantity. A VAS generally utilizes a representation of distance, such asa picture of a line with hash marks drawn at regular distance intervals,e.g., ten 1-cm intervals. For example, a patient can be asked to rank asensation of pain or itch by choosing the spot on the line that bestcorresponds to the sensation of pain or itch, where one end of the linecorresponds to “no pain” (score of 0 cm) or “no itch” and the other endof the line corresponds to “unbearable pain” or “unbearable itch” (scoreof 10 cm). This procedure provides a simple and rapid approach toobtaining quantitative information about how the patient is experiencingpain or itch. VAS scales and their use are described, e.g., in U.S. Pat.Nos. 6,709,406 and 6,432,937.

A Likert scale similarly provides a measure of a one-dimensionalquantity. Generally, a Likert scale has discrete integer values rangingfrom a low value (e.g., 0, meaning no pain) to a high value (e.g., 7,meaning extreme pain). A patient experiencing pain is asked to choose anumber between the low value and the high value to represent the degreeof pain experienced. Likert scales and their use are described, e.g., inU.S. Pat. Nos. 6,623,040 and 6,766,319.

The Lequesne index and the Western Ontario and McMaster Universities(WOMAC) osteoarthritis index assess pain, function, and stiffness in theknee and hip of OA patients using self-administered questionnaires. Bothknee and hip are encompassed by the WOMAC, whereas there is one Lequesnequestionnaire for the knee and a separate one for the hip. Thesequestionnaires are useful because they contain more information contentin comparison with VAS or Likert. Both the WOMAC index and the Lequesneindex questionnaires have been extensively validated in OA, including insurgical settings (e.g., knee and hip arthroplasty). Their metriccharacteristics do not differ significantly.

The AUSCAN (Australian-Canadian hand arthritis) index employs a valid,reliable, and responsive patient self-reported questionnaire. In oneinstance, this questionnaire contains 15 questions within threedimensions (Pain, 5 questions; Stiffness, 1 question; and Physicalfunction, 9 questions). An AUSCAN index may utilize, e.g., a Likert or aVAS scale.

Indices that are useful in the methods, compositions, and kits of theinvention for the measurement of pain include the Pain Descriptor Scale(PDS), the Visual Analog Scale (VAS), the Verbal Descriptor Scales(VDS), the Numeric Pain Intensity Scale (NPIS), the Neuropathic PainScale (NPS), the Neuropathic Pain Symptom Inventory (NPSI), the PresentPain Inventory (PPI), the Geriatric Pain Measure (GPM), the McGill PainQuestionnaire (MPQ), mean pain intensity (Descriptor DifferentialScale), numeric pain scale (NPS) global evaluation score (GES) theShort-Form McGill Pain Questionnaire, the Minnesota MultiphasicPersonality Inventory, the Pain Profile and Multidimensional PainInventory, the Child Heath Questionnaire, and the Child AssessmentQuestionnaire.

Itch can be measured by subjective measures (VAS, Lickert, descriptors).Another approach is to measure scratch which is an objective correlateof itch using a vibration transducer or movement-sensitive meters.

Cough can be measured by standard questionnaires like the LeicesterCough Questionnaire as well as validated objective instruments tomeasure cough frequency (e.g. VitaloJAK).

EXAMPLES

The following examples are intended to illustrate the invention and arenot intended to limit it.

Example 1 - Compound Syntheses General Abbreviation Definitions

ACN acetonitrile

aq. aqueous

brine saturated sodium chloride solution in water

°C degrees Celsius

δ chemical shift (ppm)

d deuterium

DCM dichloromethane

DMSO dimethyl sulfoxide

ESI electrospray ionization

Et₂O diethyl ether

EtOAc ethyl acetate

g gram

h hour

MeOH methanol

mHz megahertz

min minute

ml milliliter

MS mass spectrometry

m/z mass to charge ratio

NMR nuclear magnetic resounance

Pet ether petroleum ether

RT room temperature

TLC thin layer chromatography

UV ultraviolet light

Synthesis of 1-(2-((2, 6-dimethylphenyl)amino)-2-oxoethyl)-1-ethyl-3-phenylpiperidin-1-ium iodide:

-   Synthesis of N-(2, 6-dimethylphenyl)-2-(3-phenylpiperidin-1-yl)    acetamide:    -   To a stirred solution of 2-chloro-N-(2, 6-dimethylphenyl)        acetamide (450 mg, 2.276 mmol) in ACN (10 mL) was added K₂CO₃        (944 mg, 6.829 mmol) followed by 3-phenyl piperidine (550 mg,        3.414 mmol) and the reaction mixture was stirred at 80° C. for        15 h in a sealed tube as progress of the reaction was monitored        by TLC (50% EtOAc in pet ether, Visualization: UV). The reaction        mixture was diluted with water (150 mL) and extracted with EtOAc        (2 X 150 mL). The combined organic extracts were washed with        brine (150 mL), dried over anhydrous Na₂SO₄ and concentrated        under reduced pressure to afford crude compound which was        purified by column chromatography (eluted with 60% of EtOAc/ in        pet ether) to afford pure N-(2,        6-dimethylphenyl)-2-(3-phenylpiperidin-1-yl) acetamide (560 mg).        MS (ESI): m/z 323.19 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm        9.20 (s, 1 H), 7.32-7.18 (m, 5 H), 7.06 (s, 3 H), 3.15 - 3.13        (m, 2 H), 3.00-2.97 (m, 3 H), 2.25-2.19 (m, 2 H), 2.13 (s, 6 H),        1.82-1.73 (m, 3 H), 1.19-1.15 (m, 1 H).-   Synthesis of 1-(2-((2, 6-dimethylphenyl)    amino)-2-oxoethyl)-l-ethyl-3-phenylpiperidin-1-ium iodide:    -   To a stirred solution of N-(2,        6-dimethylphenyl)-2-(3-phenylpiperidin-1-yl) acetamide (100 mg,        0.310 mmol) in ACN (2 mL) was added ethyl iodide (0.149 ml,        1.860 mmol) at room temperature, and the resulting reaction        mixture was stirred at 90° C. for 2 days in sealed tube as        progress of the reaction was monitored by TLC (10% MeOH in DCM,        Visualization: UV). The reaction mixture was concentrated under        reduced pressure to afford crude compound which was triturated        with Et₂O (5 mL) & EtOAc (10 mL) to afford 1-(2-((2,        6-dimethylphenyl)amino)-2-oxoethyl)-1-ethyl-3-phenylpiperidin-1-ium        iodide (90 mg) as a brown solid. Mass (ESI): m/z: 351.1 [M] ⁺.        UPLC: Peak-I: 32.13%, Peak-II: 66.44%. ¹H NMR (400 MHz, DMSO-d₆)        δ ppm 10.03-9.96 (m, 1 H), 7.39 (t, 2 H), 7.29-7.33 (m, 3 H),        7.15-7.08 (m, 3 H), 4.62-4.46 (m, 1 H), 4.41-4.33 (m, 1 H),        3.99-3.87 (m, 3 H), 3.70-3.64 (m, 4 H), 2.15 (d, 7 H), 2.01-1.90        (m, 2 H), 1.78-1.75 (m, 1 H), 1.42-1.34 (m, 3 H).

Synthesis of Compounds 2A-13A: Table A

The following Table A provides additional representative examples of theinvention which were synthesized from 2-chloro-N-(2, 6-dimethylphenyl)acetamide, phenyl piperidine and the appropriate alkylating reagentemploying procedures described for compound 1A.

TABLE A Compound Structure MS (ESI): m/z 2A

351.3 [M]⁺ 3A

351.2 [M]⁺ 4A

337.0 [M]⁺ 5A

351.1 [M] ⁺ 6A

365.4 [M]⁺ 7A

395.0 [M]⁺ 8A

337.2 [M]⁺ 9A

395.2 [M]⁺ 10A

365.3 [M] ⁺

Example 2 - Inhibition of Nav1.7 Current

Representative compounds of the invention were synthesized according tothe described methods and tested for the ability to inhibitvoltage-gated sodium channels.

Cell Culture

NaV1.7 was expressed upon induction with tetracycline. Cells werecultured in DMEM containing 10% dialyzed Fetal Bovine Serum (VWR,Radnor, PA), 1% Glutamax (VWR, Radnor, PA), 1% Penicillin-Streptomycin(VWR, Radnor, PA), 100 mg/L Hygromycin (Thermo Fisher Scientific,Waltham, MA and 5 mg/L Blasticidin (Alfa Aesar, Haverhill, MA). Cellswere grown and maintained at 37° C. in a humidified environmentcontaining 10% CO₂ in air. Cells were detached from the culture flaskfor passage and harvested using 0.05% Trypsin-EDTA (Thermo FisherScientific, Waltham, MA). To induce NaV1.7, cells were induced withtetracycline (0.1 - 1 µg/mL, IBI Scientific, Peosta, IA) the day beforerecording and plated onto 24-well plates. Cells were washed with DPBS(VWR, Radnor, PA), trypsinized and then triturated five times in 10 mLof growth media to break apart cell aggregates. For one 24-well plate, 2mL of cell suspension was mixed with 23 mL of fresh growth media and0.1 - 1 µg/mL tetracycline added. 1 ml of mixed media with cells wasthen added to each well of a 24-well plate, with a 12 mm coverslipalready placed in the bottom of the well. Cells were then incubated in37° C. and 10% CO₂ overnight.

Patch Clamp Solutions & Drugs

The intracellular solution contained the following (in mM) CsCl 135,NaCl 10, EGTA 10, HEPES 10, MgC1₂ 2, adjusted to pH 7.2 with CsOH. Theexternal solution was a normal Ringer solution containing (in mM) NaCl155, HEPES 10, glucose 10, KCl 3.5, CaC1₂ 1.5, MgC1₂ 1 adjusted to pH7.4 with NaOH. CsCl is from Alfa Aesar, Haverhill, MA. All otherchemicals are from Sigma-Aldrich, St. Louis, MO. In order to test thedegree of internal block by test compounds the compounds were dissolvedin internal solution at the indicated test concentration. In controlexperiments the internal solution did not contain any compound. In orderto test the degree of external block by test compounds the compoundswere dissolved in external solution at the indicated test concentration.

Whole Cell Patch Clamp Protocol

18-24 hours after cells were induced with tetracycline, coverslips wereplaced into a chamber filled with Normal Ringer solution at roomtemperature and the chamber placed on a microscope. Pipettes were pulledfrom borosilicate glass on a P97 puller (Sutter Instrument, Novato, CA)and polished with a MF-830 Microforge (Narishige International USA, Inc,Amityville, NY) to have a resistance of 1.5-2.5 MΩ when filled with CsClinternal solution at room temperature. Healthy cells (those that areround and translucent with no visible blemishes) were chosen for sealformation. A seal was formed between the pipette and the cell, and abrief pulse of suction was used to “break in” and establish thewhole-cell configuration. The membrane potential was held at -100 mVbefore the voltage protocol began. Only cells with series resistancebetween 1.5-5 MΩ were retained for analysis. The voltage protocol was asfollows: Cells were held at -100 mV for 12 ms followed by ahyperpolarizing step to -105 mV for 12 ms to monitor the leak. Cellswere then stepped back to -100 mV for 40 ms. Cells were then depolarizedto -20 mV for 10 ms and then returned to -100 mV for 26 ms.

Internal Block by Test Compounds

Once the recording was started, the voltage protocol was run at 30second intervals for 5 minutes to get a stable baseline. This wasfollowed by four 30-second periods of 5 Hz stimulation of the samevoltage protocol separated by 1 minute of rest which was then followedby 0.33 Hz stimulation after the last train. Currents were recordedusing PatchMaster software with Heka EPC10 (HEKA Electronics, Lambrecht,Germany). Only cells with inward current amplitudes at -20 mV between400 pA and 4 nA were accepted. In addition, cells having leak currentsgreater than 10% of their current amplitudes were discarded.

Data Analysis: Internal Block

The data was plotted using the Patchmaster software (HEKA Electronics,Lambrecht, Germany) and analyzed by plotting the minimum current duringthe voltage step to -20 mV (peak inward current) as a function of time.In order to determine the degree of rundown over the course of anexperiment, the average peak inward current amplitude (2-3 points)before 5 Hz stimulation was designated as the baseline (I_(baseline)).The average peak inward current during the last 2 second of the last 5Hz train was measured (I_(test)). The control fraction current remainingwas calculated by dividing I_(test) by I_(baseline). On each recordingday three cells were tested with control internal solution and theaverage fraction of current remaining calculated (Ctrl fractioncurrent).

To determine the %block produced by test compounds applied internallythe following was done. The average peak inward current amplitude (2-3points) before 5 Hz stimulation was designated as 0% block(I_(0%block)). To correct for the current change under controlconditions, I_(0%block) was multiplied by the average Ctrl fractioncurrent remaining to get the corrected 0% block current. The averagepeak inward current during the last 2 seconds of the last 5 Hz train wasdesignated as the unblocked current (I_(unblocked)). The %block wascalculated using the following equation: (1 -I_(unblocked)/(I_(0%block) * Ctrl fraction current remaining) x 100).

Representative examples of the invention were tested for intracellularinhibition of NaV 1.7. Activity Range is % inhibition at 1 µM testconcentration: “++++” (>90%), “+++” 90- 70%, “++” (70-30%) or “+” (<30%. The results are presented below:

Compound Nav1.7 Intracellular Inhibition Compound Nav1.7 IntracellularInhibition Compound Nav1.7 Intracellular Inhibition 1A ++++ 2A ++++ 3A++++ 4A +++ 5A +++ 6A ++++ 7A ++++ 8A ++ 9A ++ 10A ++

External Block by Test Compounds

Once the recording was started, the voltage protocol was run at 30second intervals for 5 minutes to get a stable baseline. This isfollowed by 5 Hz stimulation of the same voltage protocol run until theend of experiment. The test compound is added during the 5 Hzstimulation train making sure to wait until the cell shows stablecurrent rundown rate before addition of the compound. The test compoundis added for 5 minutes before washing out with normal Ringer’s solution.Currents were recorded using PatchMaster software with Heka EPC10 (HEKAElectronics, Lambrecht, Germany). Only cells with inward currentamplitudes at -20 mV between 400 pA and 4 nA were accepted. In addition,cells having leak currents greater than 10% of their current amplitudeswere discarded.

Data Analysis: External Block

The data was plotted using the Patchmaster software (HEKA Electronics,Lambrecht, Germany) and analyzed by plotting the minimum current duringthe voltage step to -20 mV (peak inward current) as a function of time.To determine the % block produced by test compounds applied externallythe following was done. After the stable current rundown rate wasestablished during the 5 Hz stimulation train, the Rate_(rundown) wascalculated by dividing the change in peak current amplitude by time. Theaverage peak inward current amplitude (2-3 seconds) before addition ofcompound was used to determine 0% block (I_(0%block)). To correct forthe rundown, I_(0%block) is subtracted by the (Rate_(rundown)* 5 min) toget the corrected 0% block current. The average peak inward currentduring the last 2-3 seconds of the 5 minutes of compound applicationtime before washing is the unblocked current (I_(unblocked)). The %blockwas then calculated using the following equation: Fraction currentblock=1- I_(unblocked)/(I_(0%block) -Rate_(rundown)* 5 min).

Representative examples of the invention were tested for extracellularinhibition of NaV 1.7. Activity Range is % inhibition: “++++” (>90%),“+++” 90-70%, “++” (70-30%) or “+” (< 30%). The results are presentedbelow.

Compound Test Concentration Na_(v)1.7 Extracellular Inhibition 2A 10µM + 3A 10 µM ++ 5A 30 µM ++ 6A 10 µM ++ 8A 30 µM ++

Example 3 - Membrane Permeability

The PAMPA assay (pION, Inc., Woburn MA) was used to determine theability of compounds of the invention to cross an artificial lipidmembrane by passive diffusion. Test compounds were dissolved in DMSO (10mM) and diluted 200-fold in buffer (pION Inc., pH 7.4) to provide 50 uMstock solutions. Buffer (150 µL) was added to a UV blank plate and stocksolutions (150 µL) were transferred to a UV reference plate. The blankand reference spectrum were read using a spectrophotometer. Stocksolutions (200 µL) were added to the donor plate of the PAMPA sandwichplate and an accept plate painted with GIT lipid (pION Inc, 5 µL) wasplaced on top. Buffer (200 µL) was added to the acceptor plate and thePAMPA sandwich plate was incubated for 4 hours. Aliquots (150 µL) fromthe acceptor plate were added to a UV plate and read as acceptorspectrum. Aliquots (150 µL) of the donor solutions were added to a UVanalysis plate and read as donor spectrum. The permeability coefficientof test compounds was calculated using PAMPA Explorer TM software(version 3.5.0.4) based on the AUC of the reference plate, the donorplate, and the acceptor plate.

The PAMPA permeability results (10⁻⁶cm/s) of representative compoundsare reported as “+” (< 0.1 10⁻⁶ cm/s), “++”(0.1-2.0 10⁻⁶ cm/s), “+++”(2.0-10.010⁻⁶cm/s) or “++++” (>10.0 10⁻ ⁶cm/s).

Compound PAMPA (10⁻⁶cm/s) Compound PAMPA (10⁻⁶cm/s) Compound PAMPA(10⁻⁶cm/s) 2A + 3A + 4A + 5A + 6A + 7A + 8A + 9A +

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims. It will also be understood that noneof the embodiments described herein are mutually exclusive and may becombined in various ways without departing from the scope of theinvention encompassed by the appended claims.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims. It will also be understood that noneof the embodiments described herein are mutually exclusive and may becombined in various ways without departing from the scope of theinvention encompassed by the appended claims.

1. A compound represented by Formula (I)

wherein: Y⁻ is a pharmaceutically acceptable anion; n is 1, 2, 3, or 4;R^(A), R^(B), and R^(C) are each independently selected from H, D,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, OR^(I), CN, NR^(J)R^(K), NR^(L)C(O)R^(M), S(O)R^(N),S(O)₂R^(N), SO₂R^(O)R^(P), SO₂NR^(Q)R^(R), SO₃R^(S), CO₂R^(T);C(O)R^(U), and C(O)NR^(V)R^(W); each of R^(I), R^(J), R^(K), R^(L),R^(M), R^(N), R^(O), R^(P), R^(Q), R^(R) R^(S), R^(T), R ^(U), R^(V) andR^(W) is independently selected from H, D, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl; or R^(J) and R^(K) orR^(V) and R^(W) or R^(Q) and R^(R) can also be taken together with thenitrogen to which they are attached to form a substituted orunsubstituted 5, 6, 7, or 8 membered ring; R^(A), R^(B), and/or R^(C)can be taken together with the phenyl ring to which they are attachedcan form a fused bicyclic or tricyclic ring system; X¹ is selected from—CR^(X)R^(Y)—, —NR^(Z)C(O)—, —OC(O)—, —SC(O)—, — C(O)NR1A—, —C(O)O—,—C(O)—, —(O)CS—, —NR^(1A)S(O)—, —S(O)NR^(1A)—, — NR^(1A)C(O)NR^(1A)—,—S(O)—, —S(O)₂— and —NR^(Z)C(O)CR^(X)R^(Y)—; each of R^(X), R^(Y),R^(Z), and R^(1A) is independently selected from H, D, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl;each of R^(D) and R^(E) is independently selected from H, D, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheteroalkyl, and substituted or unsubstituted cycloalkyl; or R^(D) andR^(E) together with the carbon to which they are attached form asubstituted or unsubstituted C₃-C₆ cycloalkyl, substituted orunsubstituted heterocyclic, or substituted or unsubstituted heteroalkylring; or R^(D) and R^(Z) together with the carbon and the —N—C(O)— towhich they are attached form an optionally substituted 5-8-memberedlactam; R^(H) is selected from substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl; and R^(1B) is a substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl,preferably phenyl.
 2. The compound of claim 1, wherein R^(H) issubstituted or unsubstituted alkylcarboxylate or substituted orunsubstituted alkylcarboxamide.
 3. The compound of claim 1, whereinR^(H) can be a substituted or unsubstituted aralkyl or heteroarylalkyl.4. The compound of claim 1, wherein Y⁻ is bromide, chloride, or iodide.5. The compound of claim 1, wherein X¹ is —NHC(O)—.
 6. The compound ofclaim 3, wherein R^(H) is selected from a C₆₋₁₀ aralkyl or a C₅₋₁₀heteroarylalkyl, each optionally substituted with C₁₋₆ alkyl, C₃-C₆cycloalkyl, heterocyclyl, phenyl, substituted phenyl, heteroaryl,substituted heteroaryl, hydroxyl, amide, ester, sulfonamide, urea,nitrile, or halogen.
 7. The compound of claim 1, wherein R^(H) is asubstituted or unsubstituted alkyl.
 8. The compound of claim 1, whereineach of R^(A) and R^(B) is independently selected from H, halogen, andC₁₋₄ alkyl, and R^(C) is H.
 9. The compound of claim 1, wherein each ofR^(A) and R^(B) is CH₃, and R^(C) is selected from the group consistingof H, CH₃, halogen, nitrile, methoxy, and ethoxy.
 10. The compound ofclaim 1, wherein R^(1B) is phenyl.
 11. The compound of claim 1, whereinR^(D) and R^(E) are both hydrogen.
 12. The compound of claim 1, whereinR^(D) is hydrogen and R^(E) is an alkyl.
 13. The compound of claim 1,wherein n is
 1. 14. The compound of claim 1, wherein n is
 2. 15. Thecompound of claim 1, wherein n is
 3. 16. The compound of claim 1,wherein the compound is selected from the following: Compound Structure1A

2A

3A

4A

5A

6A

7A

8A

9A

10A

.
 17. A pharmaceutical composition comprising the compound of claim 1 ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 18. The composition of claim 17, wherein saidcomposition is formulated for oral, intravenous, intramuscular, rectal,cutaneous, subcutaneous, topical, transdermal, sublingual, nasal,inhalation, vaginal, intrathecal, epidural, or ocular administration.19. A method for treating pain, cough, itch, or a neurogenicinflammatory disorder in a patient, comprising administering to saidpatient an effective amount of the compound of claim
 1. 20. The methodof claim 19, wherein said pain is selected from the group consisting ofpain due to back and neck pain, lower back pain, cancer pain,gynecological and labor pain, fibromyalgia, arthritis, rheumatoidarthritis, osteoarthritis, rheumatological pains, orthopedic pains,acute and post herpetic neuralgia and other neuropathic pains (includingperipheral neuropathy), sickle cell crises, vulvodynia, perianal pain,irritable bowel disease, irritable bowel syndrome, inflammatory boweldisease, oral mucositis, esophagitis, interstitial cystitis, urethritisand other urological pains, dental pain, headaches, trigeminal trophicsyndrome, erythromelalgia, abdominal wall pain, chronic abdominal wallpain, allergic rhinitis, muscle pain, rectal pain, Levator ani syndrome,proctalgia fugax, hemorrhoid pain, stomach pain, skin ulcers, stomachulcers, burn pain, ophthalmic irritation, conjunctivitis (e.g., allergicconjunctivitis), eye redness, dry eye, dry eye syndrome (chronic ocularpain), complex regional pain syndrome, post-surgical ocular pain,postoperative pain, acute postoperative pain, and procedural pain (i.e.,pain associated with injections, draining an abscess, surgery, dentalprocedures, ophthalmic procedures, arthroscopies and use of othermedical instrumentation, cosmetic surgical procedures, dermatologicalprocedures, setting fractures, biopsies, and the like).
 21. The methodof claim 20, wherein said cough is selected from the group consisting ofcough in patients with asthma, COPD, asthma-COPD overlap syndrome(ACOS), interstitial pulmonary fibrosis (IPF), idiopathic pulmonaryfibrosis, post viral cough, post-infection cough, chronic idiopathiccough, and lung cancer.
 22. The method of claim 20, wherein said itch isselected from the group consisting of itch due to pruritus,brachioradial pruritus, chronic idiopathic pruritus, genital/analpruritus, notalgia paresthetica, scalp pruritus, allergic dermatitis,contact dermatitis, atopic dermatitis, hand eczema, poison ivy,infections, parasites, insect bites, pregnancy, metabolic disorders,liver or renal failure, drug reactions, allergic reactions, eczema,genital and anal itch, hemorrhoid itch, and cancer.
 23. The method ofclaim 20, wherein said neurogenic inflammatory disorder is selected fromthe group consisting of allergic inflammation, asthma, chronic cough,conjunctivitis, rhinitis, psoriasis, inflammatory bowel disease,interstitial cystitis, arthritis, colitis, contact dermatitis, diabetes,eczema, cystitis, gastritis, migraine headache, rosacea, sunburn,pancreatitis, chronic rhinosinusitis, traumatic brain injury,polymicrobial sepsis, tendinopathies, chronic urticaria, rheumaticdisease, acute lung injury, exposure to irritants, inhalation ofirritants, pollutants, chemical warfare agents, and atopic dermatitis.24. The method of claim 20, wherein a compound represented by Formula(I) is used in combination with one or more exogenous large porereceptor agonists.